Prokineticin 1 receptor antagonists

ABSTRACT

The present invention relates to certain novel compounds of Formula (I): 
                         
and methods for preparing these compounds, compositions, intermediates and derivatives thereof and for the treatment of prokineticin 1 or prokinetin 1 receptor mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/754,939, filed Dec. 29, 2005, which is hereby incorporated byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described herein was notfederally sponsored.

BACKGROUND OF THE INVENTION

Digestion involves the breakdown of food materials into molecules thatcan be delivered to and utilized by individual cells of the body. Thesemolecules may serve as energy sources; they may provide essentialchemical elements, such as calcium, nitrogen or iron; or they may becomplete molecules, e.g., certain amino acids, fatty acids and vitamins,that the cells need but cannot synthesize themselves. Digestion whichincorporates the processes of breakdown and assimilation of foodmaterials as well as the elimination of undigestable waste materialtakes place in a long convoluted tube that extends from the mouth to theanus, known as the gastrointestinal (GI) tract. The GI tract begins withthe oral cavity, the mouth, and continues to include the, pharynx,esophagus, stomach, small intestine, large intestine and anus. The GItract, from beginning to end, has four tissue layers: (1) the mucosa,which is the innermost layer, is made up of columnar epithelial cellsthat are in direct contact with ingested materials and facilitate fluidand electrolyte transport and digestion and absorption of nutrients, anunderlying basement membrane consisting of connective tissue and a thinlayer of smooth muscle; (2) the submucosa, which is the second innermostlayer, is made up of connective tissue containing small clusters ofnerve cells and nerve fibers, and blood and lymph vessels; (3) themuscularis externa, which is the third innermost layer, is made up oftwo separate layers of smooth muscle tissue oriented in opposingdirections and containing a vast network of nerve cell clusters andnerve fibers sandwiched in-between these layers; and (4) the serosa,which is the outermost layer consisting of a coating of connectivetissue that is in contact with the environment of the peritoneal cavityof the abdomen.

Along most of the GI tract, the muscularis externa is made up of twoopposing layers of smooth muscle, the inner layer, in which the cellularorientation is perpendicular to the long axis of the gut, and the outerlayer, in which cellular orientation is parallel to the long axis of thegut. Coordinated contractions of these muscle layers produce ring-likeconstrictions that mix food, as well as wave-like motions, known asperistalsis, that move food along the GI tract. At several points, thecircular layer of muscle thickens into heavy bands forming valve-likeconstrictions called sphincters, which by relaxing and contracting, actto regulate the passage of food from one area of the GI tract toanother.

Breakdown and assimilation of nutrients from food materials isaccomplished chiefly by the highly coordinated activities of the stomachand small intestine. The stomach is influenced by both the nervous andendocrine systems. Anticipation of food and the presence of food in themouth stimulate churning movements of the stomach and the production ofgastric juices. When food reaches the stomach, its presence causes therelease of the hormone gastrin from gastric endocrine cells into thebloodstream. Gastrin acts on the cells of the stomach to increase theirsecretion of gastric juices.

Food is converted in the stomach to a semiliquid mass as a result ofgastric juices, including pepsin, hydrochloric acid and the churningmotions. The food is then emptied into the small intestine, where thebreakdown of food is completed. The resulting nutrient molecules arethen absorbed into the circulatory system, from which they are deliveredto the individual cells. The small intestine contains a variety ofdigestive secretions, some produced by the intestinal cells and some bythe pancreas and liver. Other epithelial cells, the goblet cells of themucosa, secrete mucus. The digestive activities of the small intestineare coordinated and regulated by hormones. In addition to hormonalinfluences, the intestinal tract is also regulated by the autonomic andenteric nervous systems, which are involved in regulating the secretionof digestive enzymes, and coordinating the activities of contraction andepithelial secretion. Thus, a complex interplay of stimuli and checksand balances serves to activate digestive enzymes, adjust the chemicalenvironment and regulate the movement of ingested materials in theintestines.

The large intestine is involved in the absorption of water, sodium andother electrolytes. Some of its epithelial cells secrete mucus, whichlubricates undigested food residue. Large amounts of water enter thestomach and small intestine by osmosis from body fluids or as secretionsof the glands lining the digestive tract. When the absorption process isinterfered with and/or secretions from the mucosal glands becomesenhanced, as in diarrhea, severe dehydration can result.

Functional bowel disorders involve abnormal motility and secretionwithin organs of the GI tract, and are characterized by abdominaldiscomfort/pain. The Criteria for these disorders are summarized bygastroenterologists in the ‘Rome II criteria’ (See, for example, Rome IIDiagnostic criteria for the Functional Gastrointestinal Disorders,Second Edition, Senior Editor Douglas A. Drossman, M. D., ManagementServices, McLean, Va. (2000)). Based on these criteria the disorders arecommon and include, but are not limited to, functional dyspepsia,irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD),non-erosive reflux disease (NERD), and chronic constipation (includingcolonic inertia, idiopathic pseudoobstruction). GERD is extremelyprevalent, is usually associated with non-cardiac chest pain and may betreated with acid-suppressing agents and prokinetic agents. IBS ischaracterized by the presence of reoccurring constipation and/ordiarrhea, which can be associated with gaseous distention/bloating andabdominal discomfort/pain (Thompson, W. G. and Heaton, K. W.Gastroenterology 1980, 79, 283-288). The onset of the pain of IBS isassociated with a change in the frequency and/or form of stool and canbe relieved by defecation. IBS is an extremely prevalent condition thatoccurs to varying severity in 10-15% of the population (Saito, Y. A.;Schoenfeld, P.; and Locke, G. R. Am. J. Gastroenterol. 2002, 97,1910-1915). The pain may be treated with smooth muscle relaxants andantidepressants (Jackson, J. L.; O'Malley, P. G.; Tomkins, G.; Balden,E.; Santoro, J.; and Kroenke, K.; Am. J. Med. 2000, 108, 65-72;Jailwala, J.; Imperiale, T. F.; and Kroenke, K.; Ann. Intern. Med. 2000,133:136-147; Akehurst, R. and Kaltenthaler, E. Gut 2001, 48, 272-282;Poynard, T.; Regimbeau, C.; and Benhamou, Y.; Aliment Pharmacol. Ther.2001, 15, 355-361). Severe diarrhea predominant IBS is treated byalosetron, whereas constipation predominant IBS is treated by tegaserod.Functional dyspepsia is a disorder of the upper GI tract with symptomsexacerbated by a meal and associated with early satiety, nausea andvomiting. Although its etiology is unknown, prokinetic agents mayrelieve the symptoms of IBS. In some patients there is overlap insymptoms between GERD/NERD, functional dyspepsia and IBS. Treatments forfunctional bowel disorders, such as IBS, have low efficacy and areassociated with adverse effects. For example, alosetron is approved bythe FDA on a risk management program because it is associated with anincrease in ischemic colitis. No treatments effectively alleviate painin functional bowel disorders.

In addition to functional disorders, inflammatory bowel diseases (IBD)are common and include ulcerative colitis (UC) and Crohn's disease (CD).Although there may be a genetic component to CD, the etiology of both UCand CD is unknown. UC is a diffuse mucosal disease of the colon,characterized by inflammation and ulceration, which is associated withdiarrhea and abdominal cramping. The mucosal inflammation progressesfrom the rectal area to eventually extend through the large bowel. CD isa transmural inflammation that most frequently involves the distal smallbowel and colon. The inflammation can result in ulcers of varyinginvolvement and in severe cases can result in transmural scarring andchronic inflammation. Both infectious and dysregulated immune functionsmay contribute to disease onset. Therapies for IBD includecorticosteroids, immunosuppressives (azathioprine, mercaptopurine, andmethotrexate) and aminosalicylates (5-ASA). These therapies involvesuppression of the immune system by mimicking corticosteroids, or haveunknown mechanisms of action. Oral corticosteroid use is associated withserious adverse effects, whereas immunosuppressives and aminosalicylatesare only moderately effective. Infliximab (a chimeric monoclonalanti-tumor necrosis factor antibody) is effective in CD, however, itsuse is associated with the presence of antibodies, which reduce itsefficacy. There are currently no treatments that target the motility andsecretory abnormalities or painful sensation that are associated withgut inflammation.

The cysteine rich proteins known as Prokineticin 1 (PK1) andProkineticin 2 (PK2), as well as variants, fragments and moleculeshaving PK activity, have been identified. PK1 and PK2 have been shown tocontract gastrointestinal smooth muscle (Li, M.; Bullock, C. M.; Knauer,D. J.; Ehlert, F. J.; and Zhou, Q. Y., Mol. Pharmacol. 2001, 59,692-698), and suppress feeding (Negri, L.; Lattanzi, R.; Giannini, E.;De Felice, M.; Colucci, A. and Melchiorri, P. Brit. J. Pharmacol. 2004,142, 181-19.1). PK1 and PK2 act on both PK1 and PK2 receptors, andlimited structural changes of C-terminal cysteine-rich regions of theserelated PKs are tolerated. For example, chimeric PKs, where thecysteine-rich domains of PK1 and PK2 were exchanged between the two anda splice variant of PK2 that included a 21 residue insertion in itsC-terminal domain retained activity (Bullock, C M; Li J. D.; Zhou, Q.Y.; Mol. Pharmacol. 2004, 65(3), 582-8). A PK variant binds to receptorsof primary sensory neurons, and results in an intense sensitization ofperipheral nociceptors to thermal and mechanical stimuli (Mollay, C.;Weschelberger, C.; Mignogna, G.; Negri, L.; Melchiorri, P.; Barra, D.;Kreil, G.; Eur. J. Pharmacol. 1999, 374, 189-196; Negri, L.; Lattanzi,R.; Giannini, E.; Metere, A.; Colucci, M.; Barra, D.; Kreil, G.;Melchiorri, P.; Brit. J. Pharmacol. 2002, 137(8), 1147-54).

PK1 (also known as EG-VEGF) induces proliferation, migration andfenestration in capillary endothelial cells derived from endocrineglands. The expression of PK mRNA has been observed in steroidogenicglands, ovary, testis, adrenal and placenta. (LeCouter, J.; Kowalski,J.; Foster, J.; Hass, P., Zhang, Z.; Dillard-Telm, L., Frantz, G.,Rangell, L.; DeGuzman, L.; Keller, G. A.; Peale, F.; Gurney, A.; Hillan,K. J.; Ferrara, N. Nature 2001, 412 (6850), 877-84). In 2002 theidentification of the PK1 receptor provided a novel molecular basis forthe regulation of angiogenesis in endocrine glands (Masuda, Y.; Takatsu,Y.; Terao, Y.; Kumano, S.; Ishibashi, Y.; Suenaga, M.; Abe, M.;Fukusumi, S.; Watanabe, T.; Shintani, Y.; Yamada, T.; Hinuma, S.;Inatomi, N.; Ohtaki, T.; Onda, H.; Fujino, M.; Biochem. Biophys. Res.Commun. 2002, 293(1), 396-402; LeCouter, J.; Lin, R.; Ferrara, N.; ColdSpring Harb Symp Quant Biol. 2002, 67, 217-21). For example, adenoviraldelivery of PK1 to the mouse testis results in a potent angiogenicresponse (LeCouter, J.; Lin, R.; Tejada, M.; Frantz, G.; Peale, F.;Hillan, K. J.; Ferrara, N. Proc. Natl. Acad. Sci. USA. 2003, 100,2685-90). Recently, it was shown that PK1 mRNA is not normally expressedin colorectal normal mucosa but is detected in colorectal cancer cells(Goi, T.; Fujioka, M.; Satoh, Y.; Tabata, S.; Koneri, K.; Nagano, H.;Hirono, Y.; Katayama, K.; Hirose, K. and Yamaguchi, Cancer Res. 2004,64, 1906-1910).

Thus, PK1 receptor modulators, and in particular PK1 receptorantagonists, may be useful in the treatment and prevention of variousmammalian disease states, for example, visceral pain that is associatedwith IBS and IBD. Additionally, PK1 receptor modulators, and inparticular PK1 receptor antagonists, may be useful for the treatment ofGERD or other forms of secretory diarrhea. Additionally, PK1 receptormodulators, and in particular PK1 receptor antagonists, may be useful intreating cancer-specific angiogenesis factor in the large intestine andreproductive organs.

WO200236625 discloses PK1 and PK2 polynucleotides and polypeptides anduses thereof.

U.S. 20040156842 and corresponding U.S. Pat. No. 6,485,938 disclose theuse of peptide antagonists of PK1 and PK2 to treat inflammation in theintestine. The references disclose that the antagonists includeantibodies that specifically bind with PK1 and PK2 and receptors thatbind to amino acid sequences disclosed therein.

WO2004087054 discloses methods of modulating gastric acid or pepsinogensecretion by administering a prokineticin receptor antagonist to alterone or more indicia of gastric acid secretion. The reference disclosesthat the prokineticin receptor antagonist is a modified version of aprokineticin from any species that contains an amino acid sequence atleast 80% identical to an amino acid sequence disclosed therein.

It is an object of the present invention to provide compounds that areprokineticin 1 receptor antagonists. It is also an object of theinvention to provide a method of treating or ameliorating a conditionmediated by prokineticin 1 receptor. And, it is an object of theinvention to provide a useful pharmaceutical composition comprising acompound of the present invention useful as a prokineticin 1 receptorantagonist.

The present invention is also directed to methods for producing theinstant compounds and pharmaceutical compositions and medicamentsthereof.

The present invention is further directed to methods for treating orameliorating a Prokineticin 1-mediated disorder. In particular, themethod of the present invention is directed to treating or amelioratinga Prokineticin-mediated disorder such as, but not limited to, visceralpain that is associated with IBS and IBD, GERD and other forms ofsecretory diarrhea, and cancer-specific angiogenesis factor in the largeintestine and reproductive organs.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I):

wherein:

-   A₁ is CF₃, C₁₋₄alkoxy, aryl, aryloxy, benzofused heterocyclyl, or    heteroaryl; wherein aryl, aryloxy, and heteroaryl are optionally    substituted with pyrazol-1-yl or [1,2,3]thiadiazol-4-yl; or aryl,    aryloxy, the benzo portion of benzofused heterocyclyl, and    heteroaryl are optionally substituted with one to three substituents    independently selected from the group consisting of C₁₋₆alkyl,    hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy, halogen, nitro, halogenated    C₁₋₆alkyl, halogenated C₁₋₆alkoxy, C₁₋₆alkylthio,    C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,    cyano, hydroxy, aminocarbonyl, C₁₋₆alkylaminocarbonyl,    di(C₁₋₆alkyl)aminocarbonyl, C₁₋₆alkoxycarbonylamino,    C₁₋₆alkylcarbonyl, C₁₋₆alkylthiocarbonyl, formyl, C₁₋₆alkylsulfonyl,    C₁₋₆alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, and    di(C₁₋₆alkyl)aminosulfonyl; provided that A₁ is other than    3,5-di-t-butyl-phenyl;-   L₁ is —(CH₂)_(r)—, —CH₂C₂₋₄alkenyl-, or —CH₂CH₂X(CH₂)_(s)—, wherein    L₁ is optionally substituted with one to two substituents    independently selected from the group consisting of C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, and halogen; and, r is an integer of 1 to    5; such that r is greater than or equal to 4 when A₁ is C₁₋₄alkoxy;-   s is an integer of 1 to 3;-   X is O or S;-   D is —P-A₂;-   wherein P is —(CH₂)₁₋₂— or —CH₂CH═CH— when A₂ is phenyl, benzofused    heterocyclyl, heteroaryl, or C₃₋₈cycloalkyl; alternatively, P is    —(CH₂)₃₋₆—, when A₂ is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl;    and wherein P is optionally substituted with one to two substituents    independently selected from the group consisting of C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, and halogen;-   A₂ is hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl, benzofused    heterocyclyl, heteroaryl, tetrahydro-pyranyl, piperidinyl, or    C₃₋₈cycloalkyl; wherein phenyl, heteroaryl, the benzo portion of    benzofused heterocyclyl, and C₃₋₈cycloalkyl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,    halogenated C₁₋₆alkyl, halogenated C₁₋₆alkoxy, aryl(C₁₋₆)alkoxy,    phenyl, N-isoindole-1,3-dione, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,    C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,    cyano, hydroxy, nitro, C₁₋₆alkylcarbonyl, C₁₋₆alkylthiocarbonyl,    aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆alkyl)aminocarbonyl,    C₁₋₆alkylcarbonylamino, and a non fused C₃₋₆cycloalkyloxy; such that    no more than two substituents on A₂ are aryl(C₁₋₆)alkoxy, phenyl,    N-isoindole-1,3-dione, or a non fused C₃₋₆cycloalkyloxy;-   provided that A₂ is other than 3,5-di-t-butyl-phenyl;-   W is N or C(R_(W)); wherein R_(W) is H or C₁₋₂alkyl;-   Q is selected from the group consisting of (a) to (g), wherein

(a) is —NH(CH₂)₂—Ar₁ wherein Ar₁ is pyridinyl optionally substitutedwith one to three C₁₋₄alkyl substituents or a substituent selected fromthe group consisting of C₁₋₄alkoxy and amino;

provided that when Ar₁ is unsubstituted pyridin-3-yl or unsubstitutedpyridin-4-yl, and A₂ is 4-methoxy-phenyl, A₁ is other than unsubstitutedphenyl or 3,4-dichloro-phenyl;

(b) —NHCH(R_(z))—Ar₂ wherein R_(z) is H or C₁₋₃alkyl; Ar₂ is pyridinyl,pyrimidinyl, pyrazinyl,

1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position; andwherein Ar₂ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,trifluoromethyl, hydroxyl-C₁₋₄alkyl, amino(C₁₋₄)alkyl,(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl,C₁₋₄alkoxy, C₃₋₈cycloalkylamino, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; or Ar₂ is optionally substituted with one aminogroup and three substituents independently selected from the groupconsisting of C₁₋₄alkyl and C₁₋₄alkoxy;

wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)aminois optionally substituted with amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy, C₁₋₄alkylthio,hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 memberedheterocyclyl; wherein a nitrogen atom of the 5 to 6 memberedheterocyclyl is optionally substituted with a C₁₋₄alkyl substituent;

and wherein pyridin-2-yl and pyridin-3-yl are optionally furthersubstituted with N-pyrrolidinyl, N-piperazinyl, N-piperidinyl,N-morpholinyl, N-thiomorpholinyl, —CH₂—O—CH₂—PH, and phenyl; wherein thephenyl substituent of pyridin-2-yl and pyridin-3-yl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, and halogen;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ ispyridin-4-yl, 4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or—(CH₂)₅—, and A₁ is methoxy, A₂ is other than 4-difluoromethoxy-phenylor 4-methoxy-phenyl;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ isbenzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—,and A₁ is pyrrol-1-yl, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—,and A₁ is 4-nitro-phenyl or ethoxy, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;

provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;

provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is unsubstitutedphenyl or 3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;

provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;

provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is—(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than4-difluoromethoxy-phenyl;

provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl,3-methoxy-phenyl, 3-cyano-phenyl, 3-nitro-phenyl, and3-trifluoromethyl-4-nitro-phenyl;

provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;

and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;

(c) is —CH₂NHCH₂—Ar₃, wherein W is N or CH, and Ar₃ is pyridinyl,pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl,imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point ofattachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7position, and that the point of attachment to quinolinyl is at the 2, 3,or 4-position; wherein Ar₃ is optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₄alkyl, amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino;

and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy,or hydroxy;

(d) is —(CH₂)₂—Ar₄, wherein Ar₄ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;wherein Ar₄ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl;

and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy,or hydroxy;

(e) is —CH═CH—Ar₅; wherein Ar₅ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;wherein Ar₅ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl;

and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy,or hydroxy;

(f) is —O—CH(R₁)—Ar₆ when W is CH; or, (f) is —S—CH(R₁)—Ar₆ and W is Nor CH; wherein R₁ is hydrogen or C₁₋₄alkyl, and Ar₆ is pyridinyl,pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl,imidazo[1,2-a]pyridinyl, or quinolinyl such that the point of attachmentto 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;

wherein Ar₆ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl;

and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy,or hydroxy;

provided that when Q is —O—CH(R₁)—Ar₆, A₁ and A₂ are 4-methoxy-phenyl,and R₁ is hydrogen, Ar₆ is other than unsubstituted pyridin-2-yl or2-amino-pyridin-4-yl;

and

(g) is —X₁—(CH(R_(x)))₂—Ar₇ when W is CH; wherein X₁ is O or S, R_(x) isH or C₁₋₄alkyl, and Ar₇ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;

wherein Ar₇ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy;

provided that when Q is —O(CH₂)₂—Ar₇ and A₁ and A₂ are 4-methoxy-phenyl,Ar₇ is other than unsubstituted pyridin-2-yl or unsubstitutedpyridin-3-yl;

wherein a nitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, and Ar₇ isoptionally substituted with oxo;

-   and enantiomers, diastereomers, tautomers, solvates, and    pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a MALDI-TOF ANALYSIS of a Prokineticin-1 ligand preparationmixture. The mixture includes a four C-terminal residue truncatedproduct (MW=9172), and a full-length prokineticin-1 ligand (MW=9668).

FIG. 2 shows a cumulative concentration-response curve evoked in theshort-circuit current (Isc) response to PK1 peptide in PK1 exposed ratileal tissues mounted in Ussing-type ion flux chambers.

FIG. 3 is a graphical representation that shows that Compound 3 of thepresent invention suppresses the PK1-evoked stimulation of gut secretionin rat ileum, without inhibiting the stimulatory action of an unrelatedsecretagogue.

FIG. 4 is a graphical representation that shows that Compound 3 of thepresent invention suppresses the Cholera toxin-evoked stimulation of gutsecretion in rat ileum, without inhibiting the stimulatory action of anunrelated secretagogue.

FIG. 5 shows that Compound 3 of the present invention suppresses Vibriocholera toxin induced increased in baseline Isc of muscle-stripped ratileum mucosa.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms are intended to have the followingmeanings:

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other. Therefore, designated numbers ofcarbon atoms (e.g. C₁₋₈) shall refer independently to the number ofcarbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion ofa larger substituent in which alkyl appears as its prefix root.

As used herein, unless otherwise noted, “alkyl” whether used alone or aspart of a substituent group refers to straight and branched carbonchains having 1 to 8 carbon atoms or any number within this range. Theterm “alkoxy” refers to an —Oalkyl substituent group, wherein alkyl isas defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer tostraight and branched carbon chains having 2 to 8 carbon atoms or anynumber within this range, wherein an alkenyl chain has at least onedouble bond in the chain and an alkynyl chain has at least one triplebond in the chain. An alkyl and alkoxy chain may be substituted on acarbon atom with a group such as hydroxyl and alkoxy. In substituentgroups with multiple alkyl groups such as (C₁₋₆alkyl)₂amino- theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

“Halogenated alkyl” refers to a saturated branched or straight chainalkyl radical derived by removal of 1 hydrogen atom from the parentalkyl; the parent alkyl chain contains from 1 to 8 carbon atoms with 1or more hydrogen atoms substituted with halogen atoms up to andincluding substitution of all hydrogen atoms with halogen. Preferredhalogenated alkyl groups include trifluoromethyl substituted alkyls andperfluorinated alkyls; more preferred fluorinated alkyls includetrifluoromethyl.

“Halogenated alkoxy” refers to a radical derived from a halogenatedalkyl, radical attached to an oxygen atom with the oxygen atom havingone open valence for attachment to a parent structure.

The term “cycloalkyl” refers to saturated or partially unsaturated,monocyclic or polycyclic hydrocarbon rings of from 3 to 20 carbon atommembers (preferably from 3 to 14 carbon atom members). Examples of suchrings include, and are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. The term cycloalkylincludes a cycloalkyl ring fused to a benzene ring (benzo fusedcycloalkyl), a 5 or 6 membered heteroaryl ring (containing one of O, Sor N and, optionally, one additional nitrogen) to form a heteroarylfused cycloalkyl.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 10members in which 1 to 4 members are nitrogen or a nonaromatic cyclicring of 5 to 10 members in which zero, one or two members are nitrogenand up to two members is oxygen or sulfur; wherein, optionally, the ringcontains zero, one or two unsaturated bonds. The term heterocyclylincludes a heterocyclyl ring fused to a benzene ring (benzo fusedheterocyclyl) such as

a 5 or 6 membered heteroaryl ring (containing one of O, S or N and,optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl orcycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the samedefinition as above but absent the option of a further fused ring) orfused with the carbon of attachment of a cycloalkyl, cycloalkenyl orheterocyclyl ring to form a spiro moiety. For such compounds in whichthe heterocyclyl ring is fused to a moiety as described above, the pointof attachment is through the heterocycyl ring portion of the compound.For instant compounds of the invention, the carbon atom ring membersthat form the heterocyclyl ring are fully saturated. Other compounds ofthe invention may have a partially saturated heterocyclyl ring.Additionally, heterocyclyl includes a heterocyclic ring bridged to formbicyclic rings. Preferred partially saturated heterocyclyl rings mayhave from one to two double bonds. Such compounds are not considered tobe fully aromatic and are not referred to as heteroaryl compounds.Examples of heterocyclyl groups include, and are not limited to,pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl andpiperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6carbon members or to an unsaturated, aromatic polycyclic ring of from 10to 14 carbon members. Examples of such aryl rings include, and are notlimited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groupsfor the practice of this invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen orsulfur. In the case of 5 membered rings, the heteroaryl ring containsone member of nitrogen, oxygen or sulfur and, in addition, may containup to three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring may contain from one to three nitrogen atoms. For thecase wherein the 6 membered ring has three nitrogens, at most twonitrogen atoms are adjacent. The term heteroaryl includes a heteroarylring fused to a benzene ring (benzo fused heteroaryl) such as

a 5 or 6 membered heteroaryl ring (containing one of O, S or N and,optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ringor a 5 to 7 membered heterocyclic ring (as defined supra but absent theoption of a further fused ring). For such compounds in which theheteroaryl ring is fused to a moiety as described above, the point ofattachment is through the heteroaryl ring portion of the compound.Examples of heteroaryl groups include, and are not limited to, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroarylgroups include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl,isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group(e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates analkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine.Substituents that are substituted with multiple halogens are substitutedin a manner that provides compounds, which are stable.

The term “oxo” whether used alone or as part of a substituent grouprefers to an O═ to either a carbon or a sulfur atom. For example,phthalimide and saccharin are examples of compounds with oxosubstituents.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) it shallbe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger substituent in which alkyl appears as itsprefix root. For alkyl, and alkoxy substituents the designated number ofcarbon atoms includes all of the independent member included in therange specified individually and all the combination of ranges within inthe range specified. For example C₁₋₆ alkyl would include methyl, ethyl,propyl, butyl, pentyl and hexyl individually as well as sub-combinationsthereof (e.g. C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅,etc.).

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As used herein, the term “acyl” refers to alkylcarbonyl substituents.

As used herein, positions on a tetrahydro[1,8]naphthyridinyl substituentwill be referred to using the following numbering system:

however, one of ordinary skill in the art will recognize that thenumbering of the tetrahydro[1,8]naphthyridinyl ring system in a compounddescribed herein, such as those shown in a specific example, may differfrom that shown above.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkylaminocarbonylC₁₋₆alkyl” substituent refers to a group ofthe formula

Embodiments of the present invention include compounds of Formula (I)wherein:

-   -   (i) A₁ is aryl, heteroaryl, or a benzofused heterocyclyl        selected from the group consisting of benzo[1,3]dioxalyl and        2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are        optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₄alkyl,        C₄alkoxy, nitro, fluoro, chloro, iodo, halogenated C₁₋₄alkyl,        halogenated C₁₋₄alkoxy, and C₁₋₄alkylthio; provided that A₁ is        other than 3,5-di-t-butyl-phenyl;    -   (ii) A₁ is aryl, heteroaryl, or a benzofused heterocyclyl        selected from the group consisting of benzo[1,3]dioxalyl and        2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are        optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₃alkyl,        methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, and        methylthio;    -   (iii) A₁ is substituted phenyl, heteroaryl, or a benzofused        heterocyclyl selected from the group consisting of        benzo[1,3]dioxalyl and 2,3-dihydro-benzofuranyl; wherein        substituted phenyl and heteroaryl are optionally substituted        with one to three substituents independently selected from the        group consisting of C₁₋₃alkyl, methoxy, fluoro and methylthio;    -   (iv) A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,        benzo[1,3]dioxalyl, or 2,3-dihydro-benzofuranyl; wherein phenyl        is substituted with, and benzotriazolyl and benzofuranyl are        optionally substituted with, one to three substituents        independently selected from the group consisting of C₁₋₄alkyl,        C₁₋₄alkoxy, nitro, fluoro, chloro, iodo, halogenated C₁₋₄alkyl,        halogenated C₁₋₄alkoxy, and C₁₋₄alkylthio; provided that A₁ is        other than 3,5-di-t-butyl-phenyl;    -   (v) A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,        benzo[1,3]dioxalyl, or 2,3-dihydro-benzofuranyl; wherein phenyl        is substituted at the 4-position with methoxy, fluoro, or        methylthio; and wherein A₁ other than substituted phenyl is        optionally substituted with one to two substituents        independently selected from the group consisting of methyl,        methoxy, fluoro and methylthio;    -   (vi) L₁ is —(CH₂)_(r)—, wherein L₁ is optionally substituted        with one to two substituents independently selected from the        group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and r is 1 or 2;    -   (vii) L₁ is —CH₂—;    -   (viii) P is —(CH₂)₁₋₂— when A₂ is phenyl, benzofused        heterocyclyl, heteroaryl, or C₃₋₈cycloalkyl; alternatively, P is        —(CH₂)₄₋₆—, when A₂ is hydrogen, C₁₋₄alkoxy, or        C₁₋₄alkoxycarbonyl;    -   (ix) P is —CH₂— when A₂ is phenyl, benzofused heterocyclyl,        heteroaryl, or C₃₋₈cycloalkyl; alternatively, P is —(CH₂)₄₋₆—,        when A₂ is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl;    -   (x) A₂ is hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl,        benzofused heterocyclyl, heteroaryl other than pyridin-4-yl, or        C₃₋₈cycloalkyl; wherein phenyl, heteroaryl and C₃₋₈cycloalkyl        are optionally substituted with one to two substituents        independently selected from the group consisting of C₁₋₆alkyl,        C₁₋₆alkoxy, fluoro, chloro, halogenated C₁₋₆alkoxy, phenyl,        N-isoindole-1,3-dione, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,        C₁₋₆alkoxycarbonyl, nitro, hydroxy, and C₁₋₆alkylcarbonylamino;        such that no more than one substituent on A₂ is phenyl or        N-isoindole-1,3-dione; and provided that A₂ is other than        3,5-di-t-butyl-phenyl;    -   (xi) A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a        heteroaryl other than pyridin-4-yl; wherein phenyl and        heteroaryl are optionally substituted with one to two        substituents independently selected from the group consisting of        C₁₋₄alkyl, C₁₋₄alkoxy, fluoro, chloro, halogenated C₁₋₄alkoxy,        N-isoindole-1,3-dione, C₁₋₄alkylthio, C₁₋₄alkylsulfonyl,        C₁₋₄alkoxycarbonyl, nitro, hydroxy, and C₁₋₄alkylcarbonylamino;        such that no more than one substituent on A₂ is        N-isoindole-1,3-dione; and provided that A₂ is other than        3,5-di-t-butyl-phenyl;    -   (xii) A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a        heteroaryl other than pyridin-4-yl; wherein phenyl and        heteroaryl are optionally substituted with one to two        substituents independently selected from the group consisting of        C₁₋₄alkoxy, fluoro, halogenated C₁₋₄alkoxy, C₁₋₄alkylthio,        C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, and hydroxy;    -   (xiii) A₂ is C₁₋₄alkoxy, phenyl, 2,3-dihydro-benzofuranyl,        indolyl, benzofuranyl, pyridin-3-yl, or benzothiophenyl; wherein        A₂ other than C₁₋₄alkoxy is optionally substituted with one to        two substituents independently selected from the group        consisting of C₁₋₄alkoxy, fluoro, fluorinated C₁₋₄alkoxy,        C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, and        hydroxy;    -   (xiv) W is N or CH;    -   (xv) W is N;    -   (xvi) Q is selected from the group consisting of (a)-(g)        wherein:        -   (a) is —NH(CH₂)₂—Ar₁ wherein Ar₁ is pyridinyl substituted            with one to three C₁₋₄alkyl substituents or a substituent            selected from the group consisting of C₁₋₄alkoxy and amino;        -   (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl,            1,2,3,4-tetrahydro-[1,8]naphthyridinyl,            imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point            of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is            at the 6 or 7 position, and the point of attachment to            quinolinyl is at the 2, 3, or 4-position; and wherein Ar₂ is            optionally substituted with one to three substituents            independently selected from the group consisting of            C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy, amino,            (C₁₋₆alkyl)amino, and di(C₁₋₆alkyl)amino;        -   wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and            di(C₁₋₆alkyl)amino is optionally substituted with            (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy,            C₁₋₄alkylthio, hydroxy, a 5 to 6 membered heteroaryl, or a 5            to 6 membered heterocyclyl; wherein a nitrogen atom of the 5            to 6 membered heterocyclyl is optionally substituted with a            C₁₋₄alkyl substituent;        -   and wherein pyridin-2-yl and pyridin-3-yl are optionally            further substituted with N-pyrrolidinyl, N-piperazinyl,            N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, and phenyl;            wherein the phenyl substituent of pyridin-2-yl and            pyridin-3-yl is optionally substituted with one to three            substituents independently selected from the group            consisting of C₁₋₄alkyl, C₁₋₄alkoxy, and halogen;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is pyridin-4-yl, 4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or            4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂— or —(CH₂)₅—, and A₁ is methoxy, A₂ is other than            4-difluoromethoxy-phenyl or 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is benzotriazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₃—, and A₁ is pyrrol-1-yl, A₂ is other than            4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂—, and A₁ is 4-nitro-phenyl or ethoxy, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;        -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than            4-trifluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and            A₁ is 4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and            A₁ is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is            unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            and A₁ is 4-methoxy-phenyl, —P-A₂ is other than            —(CH₂)₅-methoxy;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            L₁ is —(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,            4-ethyl-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl,            3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is quinolin-8-yl, benzotriazol-1-yl,            3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl, 2-chloro-phenyl,            2-nitro-phenyl, 2-trifluoromethyl-phenyl,            2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl,            2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl,            2,6-difluoro-phenyl, 2,6-dichloro-phenyl,            2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            4-trifluoromethoxy-phenyl, A₂ is other than            4-difluoromethoxy-phenyl;        -   and, provided that when Q is            —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is            3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   (c) is —CH₂NHCH₂—Ar₃, wherein W is N or CH, and Ar₃ is            pyridinyl optionally substituted with amino;        -   (d) is —(CH₂)_(z)—Ar₄, wherein Ar₄ is pyridinyl, or            pyrimidinyl; wherein Ar₄ is optionally substituted with one            to two substituents independently selected from the group            consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino,            (C₁₋₆alkyl)amino, and di(C₁₋₆alkyl)amino;        -   (e) is —CH═CH-pyridinyl;        -   (f) is —O—CH(R₁)—Ar₆ when W is CH; or, (f) is —S—CH(R₁)—Ar₆            and W is N or CH; wherein R₁ is hydrogen or C₁₋₄alkyl, and            Ar₆ is pyridinyl or pyrimidinyl; wherein Ar₆ is optionally            substituted with one to three substituents independently            selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,            amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, halogen, and            aminocarbonyl;        -   and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and            di(C₁₋₆alkyl)amino is optionally substituted with amino,            (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino,            C₁₋₄alkoxy, or hydroxy;        -   provided that when Q is —O—CH(R₁)—Ar₆, A₁ and A₂ are            4-methoxy-phenyl, and R₁ is hydrogen, Ar₆ is other than            unsubstituted pyridin-2-yl or 2-amino-pyridin-4-yl; and        -   (g) is —X₁—(CH(R_(x)))₂—Ar₇ and W is CH; wherein X₁ is O,            R_(x) is H, and Ar₇ is pyridinyl or pyrimidinyl; wherein Ar₇            is optionally substituted with one to two substituents            independently selected from the group consisting of            C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and            di(C₁₋₆alkyl)amino;        -   provided that when Q is —O(CH₂)₂—Ar₇ and A₁ and A₂ are            4-methoxy-phenyl, Ar₇ is other than unsubstituted            pyridin-2-yl or unsubstituted pyridin-3-yl;        -   wherein a nitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄, Ar₆, and Ar₇            is optionally substituted with oxo;    -   (xvii) Q is selected from the group consisting of (b) and (d)        wherein:        -   (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl, or            quinolinyl; such that the point of attachment to quinolinyl            is at the 2, 3, or 4-position; and wherein Ar₂ is optionally            substituted with one to three substituents independently            selected from the group consisting of C₁₋₄alkyl,            trifluoromethyl, C₁₋₄alkoxy, amino, (C₁₋₄alkyl)amino, and            di(C₁₋₄alkyl)amino;        -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino and            di(C₁₋₄alkyl)amino is optionally substituted with            (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy,            C₁₋₄alkylthio, hydroxy, a 5 to 6 membered heteroaryl, or a 5            to 6 membered heterocyclyl;        -   and wherein pyridin-2-yl and pyridin-3-yl are optionally            further substituted with N-morpholinyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is pyridin-4-yl, 4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or            4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂— or —(CH₂)₅—, and A₁ is methoxy, A₂ is other than            4-difluoromethoxy-phenyl or 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is benzotriazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₃—, and A₁ is pyrrol-1-yl, A₂ is other than            4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂—, and A₁ is 4-nitro-phenyl or ethoxy, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;        -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than            4-trifluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and            A₁ is 4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and            A₁ is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is            unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            and A₁ is 4-methoxy-phenyl, —P-A₂ is other than            —(CH₂)₅-methoxy;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            L₁ is —(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,            4-ethyl-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl,            3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is quinolin-8-yl, benzotriazol-1-yl,            3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl, 2-chloro-phenyl,            2-nitro-phenyl, 2-trifluoromethyl-phenyl,            2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl,            2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl,            2,6-difluoro-phenyl, 2,6-dichloro-phenyl,            2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            4-trifluoromethoxy-phenyl, A₂ is other than            4-difluoromethoxy-phenyl;        -   and, provided that when Q is            —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is            3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   (d) is —(CH₂)₂—Ar₄ and W is CH; wherein Ar₄ is pyridinyl is            optionally substituted with one to two substituents            independently selected from the group consisting of            C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and            di(C₁₋₆alkyl)amino;        -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally            substituted with oxo;    -   (xviii) Q is selected from the group consisting of (b) and (d)        wherein:        -   (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridin-2-yl, pyridin-3-yl,            or pyrimidinyl; wherein Ar₂ is optionally substituted with            one to three substituents independently selected from the            group consisting of C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy,            amino, and (C₁₋₄alkyl)amino;        -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino is            optionally substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy,            or hydroxy;        -   and wherein pyridin-2-yl and pyridin-3-yl are optionally            further substituted with N-morpholinyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is pyridin-4-yl, 4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or            4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂— or —(CH₂)₅—, and A₁ is methoxy, A₂ is            4-difluoromethoxy-phenyl or 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is benzotriazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₃—, and A₁ is pyrrol-1-yl, A₂ is other than            4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂—, and A₁ is 4-nitro-phenyl or ethoxy, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;        -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than            4-trifluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and            A₁ is 4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and            A₁ is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is            unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            and A₁ is 4-methoxy-phenyl, —P-A₂ is other than            —(CH₂)₅-methoxy;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            L₁ is —(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,            4-ethyl-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl,            3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is quinolin-8-yl, benzotriazol-1-yl,            3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl, 2-chloro-phenyl,            2-nitro-phenyl, 2-trifluoromethyl-phenyl,            2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl,            2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl,            2,6-difluoro-phenyl, 2,6-dichloro-phenyl,            2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            4-trifluoromethoxy-phenyl, A₂ is other than            4-difluoromethoxy-phenyl;        -   and, provided that when Q is            —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is            3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   (d) is —(CH₂)_(z)—Ar₄ and W is CH; wherein Ar₄ is pyridinyl            is optionally substituted with amino;        -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally            substituted with oxo;    -   (xviv) Q is —NHCH₂—Ar₂ wherein Ar₂ is unsubstituted        pyridin-2-yl, 4,6-dimethyl-pyridin-3-yl, 2-amino-pyridin-3-yl,        or 2-((C₁₋₄alkyl)amino)-pyridin-3-yl;        -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino is            optionally substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy,            or hydroxy;        -   and wherein 2-amino-pyridin-3-yl is optionally further            substituted with 4,6-dimethyl or 4-methoxy;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is pyridin-4-yl, 4-t-butyl-phenyl, 3,4-dichloro-phenyl, or            4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂— or —(CH₂)₅—, and A₁ is methoxy, A₂ is other than            4-difluoromethoxy-phenyl or 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is benzotriazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₃—, and A₁ is pyrrol-1-yl, A₂ is other than            4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is            —(CH₂)₂—, and A₁ is 4-nitro-phenyl or ethoxy, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;        -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁            is 4-fluoro-phenyl, A₂ is other than            4-trifluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and            A₁ is 4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and            A₁ is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is            unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other            than 4-methoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            and A₁ is 4-methoxy-phenyl, —P-A₂ is other than            —(CH₂)₅-methoxy;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl),            L₁ is —(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than            4-difluoromethoxy-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,            4-ethyl-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl,            3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;        -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)            and A₁ is quinolin-8-yl, benzotriazol-1-yl,            3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl, 2-chloro-phenyl,            2-nitro-phenyl, 2-trifluoromethyl-phenyl,            2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl,            2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl,            2,6-difluoro-phenyl, 2,6-dichloro-phenyl,            2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            4-trifluoromethoxy-phenyl, A₂ is other than            4-difluoromethoxy-phenyl;        -   and, provided that when Q is            —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is            3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or            3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;        -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally            substituted with oxo;            and combinations of (i) through (xviv) above.

One aspect of the present invention is directed to compositionscomprising a compound of Formula (I)

wherein:

-   A₁ is CF₃, aryl, heteroaryl, or a benzofused heterocyclyl selected    from the group consisting of benzo[1,3]dioxalyl and    2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, nitro, fluoro,    chloro, iodo, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, and    C₁₋₄alkylthio; provided that A₁ is other than 3,5-di-t-butyl-phenyl;-   L₁ is —(CH₂)_(r)—, wherein L₁ is optionally substituted with one to    two substituents independently selected from the group consisting of    C₁₋₄alkyl and C₂₋₄alkenyl and r is 1 or 2;-   D is —P-A₂;-   wherein P is —(CH₂)₁₋₂— when A₂ is phenyl, benzofused heterocyclyl,    heteroaryl, or C₃₋₈cycloalkyl; alternatively, P is —(CH₂)₄₋₆—, when    A₂ is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl;-   A₂ is hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl, benzofused    heterocyclyl, heteroaryl other than pyridin-4-yl,    tetrahydro-pyranyl, piperidinyl, or C₃₋₈cycloalkyl; wherein phenyl,    heteroaryl and C₃₋₈cycloalkyl are optionally substituted with one to    two substituents independently selected from the group consisting of    C₁₋₆alkyl, C₁₋₆alkoxy, fluoro, chloro, halogenated C₁₋₆alkoxy,    phenyl, N-isoindole-1,3-dione, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,    C₁₋₆alkoxycarbonyl, nitro, hydroxy, and C₁₋₆alkylcarbonylamino;    provided that no more than one substituent on A₂ is phenyl or    N-isoindole-1,3-dione; and provided that A₂ is other than    3,5-di-t-butyl-phenyl;-   W is CH or N;-   Q is selected from the group consisting of (a)-(g) wherein:    -   (a) —NH(CH₂)₂—Ar₁ wherein Ar₁ is pyridinyl substituted with one        to three C₁₋₄alkyl substituents or a substituent selected from        the group consisting of C₁₋₄alkoxy and amino;    -   (b) is —NHCH(R_(z))—Ar₂ wherein R_(z) is H or C₁₋₃alkyl; Ar₂ is        pyridinyl, pyrimidinyl, pyrazinyl,

-   -    1,2,3,4-tetrahydro-[1,8]naphthyridinyl,        imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of        attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6        or 7 position, and the point of attachment to quinolinyl is at        the 2, 3, or 4-position; and wherein Ar₂ is optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₄alkyl,        trifluoromethyl, hydroxyl-C₁₋₄alkyl, amino(C₁₋₄)alkyl,        (C₁₋₄alkyl)amino-(C₁₋₄)alkyl, di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl,        C₁₋₄alkoxy, C₃₋₈cycloalkylamino, amino, (C₁₋₆alkyl)amino, and        di(C₁₋₆alkyl)amino; or Ar₂ is optionally substituted with one        amino group and three substituents independently selected from        the group consisting of C₁₋₄alkyl and C₁₋₄alkoxy;    -   wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and        di(C₁₋₆alkyl)amino is optionally substituted with        (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio,        hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 membered        heterocyclyl; wherein a nitrogen atom of the 5 to 6 membered        heterocyclyl is optionally substituted with a C₁₋₄alkyl        substituent;    -   and wherein pyridin-2-yl and pyridin-3-yl are optionally further        substituted with N-pyrrolidinyl, N-piperazinyl, N-piperidinyl,        N-morpholinyl, N-thiomorpholinyl, —CH₂—O—H₂—PH, and phenyl;        wherein the phenyl substituent of pyridin-2-yl and pyridin-3-yl        is optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₄alkyl,        C₁₋₄alkoxy, and halogen;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        pyridin-4-yl, 4-C₁₋₄alkyl-phenyl, or 3,4-dichloro-phenyl, A₂ is        other than 4-methoxy-phenyl; provided that when Q is        —NHCH₂(2-amino-pyridin-3-yl), and A₁ is benzotriazol-1-yl, A₂ is        other than 4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is        —(CH₂)₂—, and A₁ is 4-nitro-phenyl, A₂ is other than        4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;    -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is        4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁        is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is        unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than        4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and        A₁ is 4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is        —(CH₂)₂—, and A₁ is pyrazol-1-yl, A₂ is other than        4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,        4-ethyl-phenyl, 3-methoxy-phenyl, and 3-nitro-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is quinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,        2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,        2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,        3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,        2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,        2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or        4-trifluoromethoxy-phenyl, A₂ is other than        4-difluoromethoxy-phenyl;    -   and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)        and A₁ is 3-nitro-4-methoxy-phenyl,        2,6-difluoro-4-methoxy-phenyl, or 3,4-dichloro-phenyl, A₂ is        other than 4-methoxy-phenyl;    -   (c) is —CH₂NHCH₂—Ar₃, wherein W is N or CH, and Ar₃ is pyridinyl        optionally substituted with amino;    -   (d) is —(CH₂)₂—Ar₄, wherein Ar₄ is pyridinyl, or pyrimidinyl;        wherein Ar₄ is optionally substituted with one to two        substituents independently selected from the group consisting of        C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and        di(C₁₋₆alkyl)amino;    -   (e) is —CH═CH-pyridinyl;    -   (f) is —O—CH(R₁)—Ar₆ when W is CH; or, (f) is —S—CH(R₁)—Ar₆ and        W is N or CH; wherein R₁ is hydrogen or C₁₋₄alkyl, and Ar₆ is        pyridinyl or pyrimidinyl; wherein Ar₆ is optionally substituted        with one to three substituents independently selected from the        group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino,        (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, halogen, and        aminocarbonyl;    -   and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and        di(C₁₋₆alkyl)amino is optionally substituted with amino,        (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino,        C₁₋₄alkoxy, or hydroxy;    -   provided that when Q is —O—CH(R₁)—Ar₆, A₁ and A₂ are        4-methoxy-phenyl, and R₁ is hydrogen, Ar₆ is other than        unsubstituted pyridin-2-yl or 2-amino-pyridin-4-yl;    -   and    -   (g) is —X₁—(CH(R_(x)))₂—Ar₇ and W is CH; wherein X₁ is O, R_(x)        is H, and Ar₇ is pyridinyl or pyrimidinyl; wherein Ar₇ is        optionally substituted with one to two substituents        independently selected from the group consisting of C₁₋₄alkyl,        C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and di(C₁₋₆alkyl)amino;    -   provided that when Q is —O(CH₂)₂—Ar₇ and A₁ and A₂ are        4-methoxy-phenyl, Ar₇ is other than unsubstituted pyridin-2-yl        or unsubstituted pyridin-3-yl;    -   wherein a nitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄, Ar₆, and Ar₇ is        optionally substituted with oxo;

-   and enantiomers, diastereomers, tautomers, solvates, and    pharmaceutically acceptable salts thereof.

Another aspect of the present invention is directed to compositionscomprising a compound of Formula (I)

wherein:

-   A₁ is aryl, heteroaryl, or a benzofused heterocyclyl selected from    the group consisting of benzo[1,3]dioxalyl and    2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₃alkyl, methoxy, fluoro, chloro,    trifluoromethyl, trifluoromethoxy, and methylthio;-   L₁ is —CH₂—;-   D is —P-A₂;-   wherein P is —CH₂— when A₂ is phenyl, benzofused heterocyclyl, or    heteroaryl; alternatively, P is —(CH₂)₄₋₆, when A₂ is C₁₋₄alkoxy;-   A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl    other than pyridin-4-yl; wherein phenyl and heteroaryl are    optionally substituted with one to two substituents independently    selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, fluoro,    chloro, halogenated C₁₋₄alkoxy, N-isoindole-1,3-dione,    C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro,    hydroxy, and C₁₋₄alkylcarbonylamino; provided that no more than one    substituent on A₂ is N-isoindole-1,3-dione; and provided that A₂ is    other than 3,5-di-t-butyl-phenyl;-   W is N or CH;-   Q is selected from the group consisting of (b) and (d) wherein:    -   (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl, or        quinolinyl; such that the point of attachment to quinolinyl is        at the 2, 3, or 4-position; and wherein Ar₂ is optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₄alkyl,        trifluoromethyl, C₁₋₄alkoxy, amino, (C₁₋₄alkyl)amino, and        di(C₁₋₄alkyl)amino;    -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino and        di(C₁₋₄alkyl)amino is optionally substituted with        (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio,        hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 membered        heterocyclyl;    -   and wherein pyridin-2-yl and pyridin-3-yl are optionally further        substituted with N-morpholinyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        pyridin-4-yl, 4-C₁₋₃alkyl-phenyl, or 3,4-dichloro-phenyl, A₂ is        other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;    -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is        4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁        is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is        unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than        4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and        A₁ is 4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is 4-methoxy-phenyl, A₂ is other than 2-ethyl-phenyl,        4-ethyl-phenyl, 3-methoxy-phenyl, and 3-nitro-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is quinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,        2-fluoro-phenyl, 2-chloro-phenyl, 2-trifluoromethyl-phenyl,        2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl,        2,6-difluoro-phenyl, 2,6-dichloro-phenyl,        2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or        4-trifluoromethoxy-phenyl, A₂ is other than        4-difluoromethoxy-phenyl;    -   and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)        and A₁ is 3-nitro-4-methoxy-phenyl,        2,6-difluoro-4-methoxy-phenyl, or 3,4-dichloro-phenyl, A₂ is        other than 4-methoxy-phenyl;    -   (d) is —(CH₂)₂—Ar₄ and W is CH; wherein Ar₄ is pyridinyl is        optionally substituted with one to two substituents        independently selected from the group consisting of C₁₋₄alkyl,        C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and di(C₁₋₆alkyl)amino;    -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally substituted        with oxo;    -   and enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

A further aspect of the present invention is directed to compositionscomprising a compound of Formula (I) wherein:

-   A₁ is substituted phenyl, heteroaryl, or a benzofused heterocyclyl    selected from the group consisting of benzo[1,3]dioxalyl and    2,3-dihydro-benzofuranyl; wherein substituted phenyl is substituted    with, and heteroaryl is optionally substituted with, one to three    substituents independently selected from the group consisting of    C₁₋₃alkyl, methoxy, fluoro and methylthio;-   L₁ is —CH₂—;-   D is —P-A₂; wherein P is —CH₂ when A₂ is phenyl, benzofused    heterocyclyl or heteroaryl; alternatively, P is —(CH₂)₄₋₆—, when A₂    is C₁₋₄alkoxy;-   A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl    other than pyridin-4-yl; wherein phenyl and heteroaryl are    optionally substituted with one to two substituents independently    selected from the group consisting of C₁₋₄alkoxy, fluoro,    halogenated C₁₋₄alkoxy, C₁₋₄alkylthio, C₁₋₄alkylsulfonyl,    C₁₋₄alkoxycarbonyl, nitro, and hydroxy;-   W is N or CH;-   Q is selected from the group consisting of (b) and (d) wherein:    -   (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridin-2-yl, pyridin-3-yl, or        pyrimidinyl; wherein Ar₂ is optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy, amino, and        (C₁₋₄alkyl)amino;    -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino is optionally        substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, or hydroxy;    -   and wherein pyridin-2-yl and pyridin-3-yl are optionally further        substituted with N-morpholinyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        pyridin-4-yl, 4-C₁₋₃alkyl-phenyl or 3,4-dichloro-phenyl, A₂ is        other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;    -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is        4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁        is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(pyridin-4-yl), and A₁ is        3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and        A₁ is 4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is 4-methoxy-phenyl, provided that when Q is        —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is quinolin-8-yl,        benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl,        2-chloro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl,        2,6-dichloro-phenyl, 2-chloro-4-fluoro-phenyl, or        2,6-difluoro-4-methoxy-phenyl, A₂ is other than        4-difluoromethoxy-phenyl;    -   and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl)        and A₁ is 2,6-difluoro-4-methoxy-phenyl or 3,4-dichloro-phenyl,        A₂ is other than 4-methoxy-phenyl;    -   (d) is —(CH₂)₂—Ar₄ and W is CH; wherein Ar₄ is pyridinyl is        optionally substituted with amino;    -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally substituted        with oxo;    -   and enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Embodiments of the present invention are even further directed tocompositions comprising a compound of Formula (I) wherein:

-   A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,    benzo[1,3]dioxalyl or 2,3-dihydro-benzofuranyl; wherein phenyl is    substituted at the 4-position with methoxy, fluoro, or methylthio;    and wherein A₁ other than substituted phenyl is optionally    substituted with one to two substituents independently selected from    the group consisting of methyl, methoxy, fluoro and methylthio;-   L₁ is —CH₂—;-   D is —P-A₂;-   wherein P is —CH₂— when A₂ is phenyl, 2,3-dihydro-benzofuranyl,    indolyl, benzofuranyl, pyridin-3-yl, or benzothiophenyl;    alternatively, P is —(CH₂)₄₋₆, when A₂ is C₁₋₄alkoxy;-   A₂ is C₁₋₄alkoxy, phenyl, 2,3-dihydro-benzofuranyl, indolyl,    benzofuranyl, pyridin-3-yl, or benzothiophenyl; wherein A₂ other    than C₁₋₄alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₄alkoxy, fluoro, fluorinated C₁₋₄alkoxy, C₁₋₄alkylthio,    C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, and hydroxy;-   W is N or CH;-   Q is —NHCH₂—Ar₂ wherein Ar₂ is unsubstituted pyridin-2-yl,    4,6-dimethyl-pyridin-3-yl, 2-amino-pyridin-3-yl, or    2-((C₁₋₄alkyl)amino)-pyridin-3-yl;    -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino is optionally        substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, or hydroxy;    -   and wherein 2-amino-pyridin-3-yl is optionally further        substituted with 4,6-dimethyl or 4-methoxy;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        pyridin-4-yl or 4-methyl-phenyl, A₂ is other than        4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;    -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is        4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁        is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and        A₁ is 4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is 4-methoxy-phenyl, A₂ is other than 3-methoxy-phenyl or        3-nitro-phenyl; and    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally substituted        with oxo;    -   and enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Embodiments of the present invention are even further directed tocompositions comprising a compound of Formula (I) wherein:

-   A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,    benzo[1,3]dioxalyl or 2,3-dihydro-benzofuranyl; wherein phenyl is    substituted at the 4-position with methoxy, fluoro, or methylthio;    and wherein A₁ other than substituted phenyl is optionally    substituted with one to two substituents independently selected from    the group consisting of methyl, methoxy, fluoro and methylthio;-   L₁ is —CH₂—;-   D is —P-A₂;-   wherein P is —CH₂— when A₂ is phenyl, 2,3-dihydro-benzofuranyl,    indolyl, benzofuranyl, pyridin-3-yl, or benzothiophenyl;    alternatively, P is —(CH₂)₄₋₆—, when A₂ is C₁₋₄alkoxy;-   A₂ is C₁₋₄alkoxy, phenyl, 2,3-dihydro-benzofuranyl, indolyl,    benzofuranyl, pyridin-3-yl, or benzothiophenyl; wherein A₂ other    than C₁₋₄alkoxy is optionally substituted with one to two    substituents independently selected from the group consisting of    C₁₋₄alkoxy, fluoro, fluorinated C₁₋₄alkoxy, C₁₋₄alkylthio,    C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, and hydroxy;-   W is N;-   Q is —NHCH₂—Ar₂ wherein Ar₂ is unsubstituted pyridin-2-yl,    4,6-dimethyl-pyridin-3-yl, 2-amino-pyridin-3-yl, or    2-((C₁₋₄alkyl)amino)-pyridin-3-yl;    -   wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino is optionally        substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, or hydroxy;    -   and wherein 2-amino-pyridin-3-yl is optionally further        substituted with 4,6-dimethyl or 4-methoxy;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        pyridin-4-yl or 4-methyl-phenyl, A₂ is other than        4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl;    -   provided that when Q is —NHCH₂(6-amino-pyridin-2-yl), and A₁ is        4-fluoro-phenyl, A₂ is other than 4-trifluoromethoxy-phenyl;    -   provided that when Q is —NHCH₂(6-methyl-pyridin-2-yl), and A₁ is        4-methoxy-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(imidazo[1,2-a]pyridinyl), and A₁        is 4-fluoro-phenyl, A₂ is other than 4-methoxy-phenyl;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and        A₁ is 4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy;    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is 4-methoxy-phenyl, A₂ is other than 3-methoxy-phenyl or        3-nitro-phenyl; and    -   provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁        is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;    -   wherein a nitrogen atom of Ar₂ and Ar₄ is optionally substituted        with oxo;    -   and enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

A further embodiment of the present invention is directed to apharmaceutical composition comprising Formula (I)

selected from the group consisting of

-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is

-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is

-   a compound of Formula (I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂,    D is —(CH₂)₅OCH₃, W is N, and Q is

-   a compound of Formula (I) wherein A₁ is 3,4-dichloro-phenyl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(pyridin-2-yl)ethyl-amino;-   a compound of Formula (I) wherein A₁ is 3,4-dichloro-phenyl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    5-amino-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4-amino-pyrimidin-5-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-amino-pyridin-3-ylmethyl-aminomethyl;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-quinolin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-amino-pyridin-3-yl)-ethylamino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-pyrrolidinyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-piperazinyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-piperidinyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-methylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-n-propylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-n-butylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-morpholino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-thiomorpholino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-ethylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-N-morpholino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    1,2,3,4-tetrahydro-[1,8]naphthyridin-7-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-2-yl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methylthio-phenyl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-(4-fluoro-phenyl)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-hydroxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-amino-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-cyclohexylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    N-oxo-2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-hydroxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-n-propylamino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxycarbonyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methylcarbonylamino-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-trifluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    pyridin-4-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is phenyl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-cyano-phenyl, L₁ is CH₂, D    is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-trifluoromethoxy-phenyl,    L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-ethoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-nitro-phenyl, L₁ is CH₂, D    is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is    CH(allyl), D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-aminocarbonyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    N-oxo-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-hydroxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-5-phenyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-4-methoxy-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-methyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4-methyl-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-ethyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-trifluoromethyl-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    3-methyl-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methylthio-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(3-methyl-butylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(tetrahydro-furan-2-ylmethyl)-amino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(furan-2-ylmethyl-amino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(N-ethyl-pyrrolidin-2-ylmethyl-amino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is phenyl, L₁ is CH₂CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is phenoxy, L₁ is CH₂CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    2,3-dihydro-benzo[1,4]dioxin-2-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-nitro-phenyl, L₁ is    CH₂CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methythio-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is pyridin-4-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzofuran-2-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 5-methoxy-n-pentyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is n-hexyl, W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-cyano-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-nitro-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-ethyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-trifluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-cyano-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-iodo-phenyl, L₁ is CH₂, D    is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-pyrazol-1-yl-phenyl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-trifluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein    A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 2-methoxy-phenylmethyl, W is    N, and Q is 2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-methoxycarbonyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-(4-methoxy-phenyl)-ethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 6-methoxy-pyridin-3-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-trifluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-trifluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methylthio-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is pyridin-4-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzofuran-2-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is n-hexyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 6-methoxy-pyridin-3-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-trifluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-ethoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-nitro-phenyl, L₁ is CH₂, D    is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is    CH(allyl), D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-fluoro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is pyridin-4-ylmethyl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-amino-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-fluoro-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-chloro-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    N-oxo-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is indol-3-yl, L₁ is CH₂CH₂, D    is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    2,3-dihydro-benzo[1,4]dioxin-2-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is pyridin-3-ylmethoxy;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-trifluoromethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-nitro-4-methoxy-phenyl, L₁    is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzofuran-5-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-5-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzofuran-5-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-5-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methanesulfonyl-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methanesulfonyl-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-t-butoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-nitro-4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-nitro-4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-4-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-4-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzothiophen-5-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenoxy, L₁ is    CH₂CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is benzothiophen-5-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzothiophen-5-yl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzothiophen-5-yl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    6-n-propylamino-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    6-amino-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-cyclohexylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-cyclohexylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3,4-dichloro-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-(isoindol-1,3-dione-2-yl)-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-methoxycarbonyl-n-propyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-pyridin-2-yl-ethylamino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-4-ylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    6-amino-pyridin-2-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-pyrazol-1-yl-phenyl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-iodo-phenyl, L₁ is CH₂, D    is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methyl-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-cyano-phenyl, L₁ is CH₂, D    is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is phenoxy, L₁ is CH₂CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-fluoro-phenoxy, L₁ is    CH₂CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    4-[1,2,3]thiadiazol-4-yl-phenyl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is 2-pyridin-3-yl-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-6-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-7-ylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is indol-7-ylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methylthio-phenyl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzothiophen-5-yl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methylthio-phenyl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2-cyano-phenyl, L₁ is CH₂, D    is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-hydroxy-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methylcarbonyloxy-phenyl,    L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenyl, W is CH, and Q is 2-pyridin-4-yl-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenyl, W is CH, and Q is cis-2-pyridin-4-yl-vinyl;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂,    D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is 2-pyridin-2-yl-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    imidazo[1,2-a]pyridin-8-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-(2-aminocarbonyl-pyridin-3-yl)-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-amino-pyridin-3-ylmethoxy;-   a compound of Formula (I) wherein A₁ is 4-hydroxymethyl-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 2-methoxy-phenyl, L₁ is CH₂,    D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-aminocarbonyl-phenyl, L₁    is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    2,6-difluoro-4-methoxy-phenyl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo[1,2,3]thiadiazol-5-yl,    L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is methoxy, L₁ is (CH₂)₅, D is    4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is methoxy, L₁ is (CH₂)₅, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-(2-amino-pyridin-3-yl)-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2,4-dimethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    4-methyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethoxy;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-fluoro-4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 3-fluoro-4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-fluoro-4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-fluoro-4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    2,3-dihydro-benzo[1,4]dioxin-6-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    2,3-dihydro-benzo[1,4]dioxin-6-yl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    pyridin-3-ylmethylthio;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 2-methyl-2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(N-piperidinyl)-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-(4-amino-pyridin-3-yl)-ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-(pyridin-4-yl)-ethylamino;-   a compound of Formula (I) wherein A₁ is    1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo[1,2,3]thiadiazol-5-yl,    L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 3-fluoro-4-methoxy-phenyl,    L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is    CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is    CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is    1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-(6-amino-pyridin-2-yl)ethyl;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 5-methoxy-n-pentyl, W is N, and Q is    2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    1-(2-amino-pyridin-4-yl)-ethoxy;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is    N-oxo-2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is    4-difluoromethoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    4,6-dimethyl-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is    4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is N, and Q is    2-amino-pyridin-3-ylmethyl-amino;-   a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂,    D is 4-methoxy-phenylmethyl, W is CH, and Q is    2-amino-pyrimidin-4-ylmethoxy;-   a compound of Formula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl,    L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is    N-oxo-2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino;    and combinations thereof.

Additional embodiments of the present invention include those compoundswherein the substituents are selected from one or more of the variablesdefined herein (i.e. A₁, L₁, s, X, P, A₂, W, and Q) are independentlyselected to be any individual substituent or any subset of substituentsselected from the complete list as defined herein.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts well known to thosein the art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates areintended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient, or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavouring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

The instant pharmaceutical composition will generally contain a perdosage unit (e.g., tablet, capsule, powder, injection, teaspoonful andthe like) from about 0.001 to about 50 mg/kg. In one embodiment, theinstant pharmaceutical composition contains a per dosage unit of fromabout 0.01 to about 20 mg/kg of compound, and preferably from about 0.05to about 10 mg/kg. Methods are known in the art for determiningtherapeutically effective doses for the instant pharmaceuticalcomposition. The therapeutically effective amount for administering thepharmaceutical composition to a human, for example, can be determinedmathematically from the results of animal studies.

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range from about 0.1mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or,more particularly from about 10 mg to about 500 mg of active ingredientin a regimen of about 1 to 4 times per day for an average (70 kg) human;although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the conditions being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe subject to be treated.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as prokineticin receptor antagonists is required for asubject in need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention.

As antagonists of a Prokineticin 1 receptor, the compounds of Formula(I) are useful in methods for treating or preventing a disease orcondition in a mammal which disease or condition is affected by theantagonistic activity of one or more Prokineticin 1 receptors. Suchmethods comprise administering to a mammal in need of such treatment orprevention a therapeutically effective amount of a compound, salt orsolvate of Formula (I). The compounds of Formula (I) are useful inmethods for preventing or treating gastrointestinal (GI) diseases,cancers of the GI tract and reproductive organs, and pain. Examples ofGI diseases to be within the scope of the present invention include, butare not limited to: irritable bowel syndrome (IBS, includingdiarrhea-predominant, as well as alternating diarrhea/constipation formsof IBS), inflammatory bowel disease (IBD, including ulcerative colitis,and Crohn's disease), and GERD and secretory bowel disorders induced bypathogens. Examples of cancers within the scope of the present inventioninclude, but are not limited to, testicular cancer, ovarian cancer,Leydig cell carcinoma, and cancers of the small or large bowel. Anexample of pain to be covered within the scope of the present invention,is, but not restricted to, visceral hyperalgesia often associated withIBS and IBD.

While the present invention comprises compositions comprising one ormore of the compounds of Formula (I) the present invention alsocomprises compositions comprising intermediates used in the manufactureof compounds of Formula (I).

Representative IUPAC names for the compounds of the present inventionwere derived using the ACD/LABS SOFTWARE™ Index Name Pro Version 4.5nomenclature software program provided by Advanced ChemistryDevelopment, Inc., Toronto, Ontario, Canada.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

-   AIBN=2,2′-azobisisobutyronitrile-   Boc=tert-butoxycarbonyl-   BuLi=n-butyllithium-   Cpd or Cmpd=compound-   d=day/days-   DCM=dichloromethane-   DIAD=diisopropyl azodicarboxylate-   DIPEA or DIEA=diisopropylethylamine-   DMEM=Dulbecco's Modified Eagle Medium-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc=ethyl acetate-   EtOH=ethanol-   h=hour/hours-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   LDA=lithium diisopropylamide-   M=molar-   MeCN=acetonitrile-   MeOH=methanol-   min=minutes-   NaOMe=sodium methoxide-   NBS=N-bromosuccinimide-   PyBOP=benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium    hexafluorophosphate-   rt/RT=room temperature-   TBAF=tetra-n-butylammonium fluoride-   TEBA=benzyltriethylammonium chloride-   THF=tetrahydrofuran-   TFA=trifluoroacetic acid-   UHP=urea-hydrogen peroxide addition complex-   μw=microwave

General Schemes

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follow. The starting materials andreagents used in the schemes that follow are understood to be eithercommercially available or prepared by methods known to those skilled inthe art. Since the schemes are an illustration, the invention should notbe construed as being limited by the chemical reactions and conditionsexpressed.

Scheme A describes the preparation of certain compounds of the presentinvention wherein Q of Formula (I) is (a) or (b) and W is N. Morespecifically, Q is —NH(CH₂)₂Ar₁ or —NHCH(R_(z))—Ar₂. In Scheme A, n is 1or 2 and Ar_(m) is Ar₁ or Ar₂, such that when n is 2, Ar_(m) is Ar₁, andwhen n is 1 and R_(z) is H or C₁₋₃alkyl, Ar_(m) is Ar₂.

A compound of formula A1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula A1 may be methylated with a methylating agent suchas methyl iodide in a polar solvent such as methanol to give a compoundof formula A2. A compound of formula A2 may be condensed with anappropriately substituted isocyanate such as N-chlorocarbonyl isocyanatein the presence of excess of a tertiary amine such asdiisopropylethylamine to give a triazine of formula A3. A compound offormula A3 may be alkylated with a compound of formula A4, which iseither commercially available or may be prepared by known methodsdescribed in the scientific literature, wherein LG₁ is a leaving group,using conventional chemistry known to one versed in the art. Forinstance, when LG₁ is a hydroxy group, compound A4 may be coupled with acompound of formula A3 in the presence of a coupling agent such as DIADin a non-alcoholic polar solvent such as THF or methylene chloride.Alternatively, LG₁ may be a halide, tosylate, or the like such that LG₁is displaced by the amino portion of a compound of A3 to give a compoundof formula A5. The Q-portion of a compound of Formula (I)-A may beinstalled by treating a compound of formula A5 with a compound offormula A6 or A6′ to afford a compound of Formula (I)-A or (I)-A′,respectively.

Scheme A-1 describes the synthesis of intermediates of formula A6.

A compound of formula A-1a is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula A-1a may be reduced under various reactionconditions, such as Raney Nickel with hydrazine or under a pressurizedatmosphere of hydrogen gas in the presence of an organometallic catalystsuch as Pd/C, to afford a compound of formula A6.

Scheme B illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (d) or (e) and W is N. Morespecifically, Q is —(CH₂)₂Ar₄ or —CH═CH—Ar₅. In Scheme B, Ar_(v) is Ar₄or Ar₅.

A compound of formula B1 (either commercially available or prepared byknown methods described in the scientific literature) may be treatedwith a base followed by alkylation with a compound of formula A4 toafford a compound of formula B2. Treatment of a compound of formula B2with an aqueous base such as hydroxide gives a compound of formula B3,which upon treatment with ammonia or its equivalent provides a compoundof formula B4. The compound of formula B4 may then be condensed with acompound of formula B5 to form a triazine compound of formula B6.

Using conventional reagents and methods known to one of ordinary skillin the art, the carboxy group of a compound of formula B6 may be reducedto its corresponding alcohol, followed by oxidation to an aldehyde offormula B7. The secondary amino group of the triazinyl ring may bealkylated with a compound of formula B8 using coupling chemistry orstandard alkylation chemistry to afford a compound of formula B9. Thealdehyde portion of the compound may participate in a Wittig olefinationwith a compound of formula B10 to provide a compound of formula Formula(I)-B1. The compound of formula (I)-B1 can be reduced under standardhydrogenation conditions to afford a compound of Formula (I)-B2.

Scheme C illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (d) or (e) and W is C(R_(W)).

A compound of formula C1 (either commercially available or prepared byknown methods described in the scientific literature) may be condensedwith a compound of formula C2 with heating, wherein LG₂ is C₁₋₄alkoxy,chloro, or the like, to form a compound of formula C3. Compound C3 canbe reacted with phosphorus oxybromide with heating to provide abromo-uracil of formula C4. A compound of formula C4 may be alkylatedwith a compound of formula B8 to provide a compound of formula C5. Acompound of formula C5 may be coupled with a compound of formula C6 inthe presence of an organometallic reagent such astetrakis(triphenylphosphine)-palladium to yield a compound of formulaC7. Hydrogenation of a compound of formula C7 provides a compound offormula Formula (I)-C1 which may be further reduced by prolongedexposure to hydrogenation conditions to yield a compound of Formula(I)-C2. Alternatively, a compound of formula C7 may be converteddirectly to a compound of formula (I)-C2 using conventionalhydrogenation reagents and methods. One of ordinary skill in the artwill recognize that the duration of exposure of a compound tohydrogenation conditions is one way of controlling the degree ofreduction of an alkyne to an alkene or alkane.

Scheme D illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (a) or (b) and W is C(R_(W)).Scheme D also illustrates the general synthesis of compounds of thepresent invention wherein Q if Formula (I) is (g) and W is C(R_(W)).

A compound of formula C3 may be treated with phosphorus oxychloride,PCl₅, or the like, with heating to afford a compound of formula D1;alternatively, the bromo analog (Formula C4) may be used in thissynthetic sequence. A compound of formula B8 may be used to install—P-A₂ via conventional alkylation procedures as described herein. Acompound of formula D2 may be elaborated via a nucleophilic displacementof the chloride (or bromide) with an amine of formula A6 (wherein Ar_(m)is defined as Ar₁ or Ar₂) to afford a compound of Formula (I)-D3. Acompound of formula D2 may be elaborated via a nucleophilic displacementof the chloride (or bromide) under basic conditions with alcohol D4 toprovide a compound of Formula (I)-D2 (when X₁=O). A compound of formulaD2 may also be elaborated via a nucleophilic displacement of thechloride (or bromide) under basic conditions with a compound of formulaD3 to provide a compound of Formula (I)-D1 (when X₁=S).

Scheme E depicts the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is —S—CH(R₁)Ar₆ of (f) or Q is—S(CH(R_(x)))₂—Ar₇ of (g), and W is N.

A compound of formula E1 (either commercially available or prepared byknown methods described in the scientific literature) may be alkylatedunder basic conditions with a compound of formula E2 (wherein Q₁ is—CH(R₁)Ar₆ or —(CH(R_(x)))₂Ar₇) to provide a compound of formula E3. Acompound of formula E3 may be condensed with an appropriatelysubstituted isocyanate such as N-chlorocarbonyl isocyanate in thepresence of excess tertiary amine such as diisopropylethylamine to givea triazine of formula E4. A compound of formula E4 may be alkylated witha compound of formula A4 to provide a compound of Formula (I)-E.

Scheme F illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (c) and W is CH.

A compound of formula F1 (either commercially available or prepared byknown methods described in the scientific literature) may be condensedwith an O-alkylated isourea to afford a cyclic compound of formula F2.The amino functionality of a compound of formula F2 may be deprotonatedselectively with a base such as lithium hydride and subsequently treatedwith a compound of formula A4. The O-demethylation of the alkylatedcompounds formula F2 affords compounds of formula F3. Using conventionaloxidation chemistry, the methyl substituent of a compound of formula F3may be converted to its corresponding aldehyde, affording a compound offormula F4. The secondary amino group may be substituted with —P-A₂ ofFormula (I) using coupling chemistry or standard alkylation with acompound of formula B8 to afford a compound of formula F5. A reductiveamination with a compound of formula F6 may afford a compound of Formula(I)-F.

Scheme G illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (c) and W is N.

A reductive amination of a compound of formula F6 with a compound offormula B9 may afford a compound of Formula (I)-G.

Scheme H illustrates the general synthesis of compounds of the presentinvention wherein Q of Formula (I) is (a) or (b) and W is C(R_(W)),wherein R_(W) is C₁₋₂alkyl, and wherein Ar_(m) is Ar₁ or Ar₂ aspreviously defined.

Compound D2 may be reacted with an ammonium salt or an ammoniumequivalent to provide a compound of formula H1. The amino functionalityof a compound of formula H1 may be protected with an appropriate aminoprotecting group to provide a compound of formula H2. Acylation of acompound of formula H2 with a compound of formula H3 (wherein R_(ww) maybe H or methyl) may give a compound of formula H4. Reduction of thecarbonyl group of a compound of formula H4 using standard procedures mayprovide a compound of formula H5. Removal of the amino protecting group(PG), followed by alkylation of the amino group with a compound offormula H6 provides a compound of Formula (I)-H.

In preparing compounds of Formula (I) wherein A₂ is piperidinyl, astandard protecting group such as N-boc can be used to protect the —NH—in the piperidinyl ring in the synthetic steps shown above. A standarddeprotection step can be used after the last step in each scheme toprovide compounds of Formula (I) wherein A₂ is piperidinyl.

SPECIFIC EXAMPLES

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The instant compounds may also beused as intermediates in subsequent examples to produce additionalcompounds of the present invention. No attempt has been made to optimizethe yields obtained in any of the reactions. One skilled in the artwould know how to increase such yields through routine variations inreaction times, temperatures, solvents and/or reagents.

Reagents were purchased from commercial sources. Nuclear magneticresonance (NMR) spectra for hydrogen atoms were measured in theindicated solvent with (TMS) as the internal standard on aBruker-Biospin Inc. DRX 500 (500 MHz) or DPX 300 (300 MHz) spectrometer.The values are expressed in parts per million downfield from TMS. Themass spectra (MS) were determined on a Micromass Platform LCspectrometer, an Agilent LC spectrometer or a Micromass LCT spectrometerusing electrospray techniques. Microwave accelerated reactions wereperformed using a CEM Discover microwave instrument, and were containedin a sealed pressure vessel unless otherwise noted. Stereoisomericcompounds may be characterized as racemic mixtures or as separatediastereomers and enantiomers thereof using X-ray crystallography andother methods known to one skilled in the art. Unless otherwise noted,the materials used in the examples were obtained from readily availablecommercial suppliers or synthesized by standard methods known to oneskilled in the art of chemical synthesis. The substituent groups, whichvary between examples, are hydrogen unless otherwise noted.

Example 1 2-amino-3-methylaminopyridine (Cpd 1a)

2-Amino-3-methylaminopyridine (Cpd 1a). 2-amino-3-cyanopyridine (3.0 g,25.2 mmol) was dissolved in 2N NH₃ in methanol (50 mL) and the solutionwas added to a Parr reaction vessel containing 10% Palladium on charcoal(500 mg) under argon. The reaction was run on a Parr hydrogenationapparatus at 55 psi until the uptake of hydrogen had ceased (˜12 hours).Upon completion, the catalyst was removed via filtration through pad ofdiatomaceous earth. The pad was rinsed with methanol (3×50 mL) and thefiltrate was reduced in vacuo to provide Compound 1a as a yellow solid.The crude mixture was used in further synthesis without additionalpurification.

Example 2 3-Aminomethyl-4,6-dimethylpyridine (Cpd 2a)

4,6-Dimethylnicotinonitrile (1.0 g, 7.6 mmol) was dissolved in ethanol(35 mL) and the mixture was treated with Raney nickel (5 mL, slurry inwater) and hydrazine hydrate (3.8 mL, 75.6 mmol). The solution wasstirred overnight at room temperature. Compound 2a was obtained byfiltering the reaction mixture through a pad of diatomaceous earth,which was rinsed with methanol (3×50 mL). The filtrate was dried overNa₂SO₄, filtered and concentrated under reduced pressure to affordCompound 2a. The compound was used without additional purification. M+(ES+)=137.1 ¹H NMR (DMSO, d₆) δ 2.35 (s, 3H), 2.42 (s, 3H), 4.01 (s,2H), 7.13 (s, 1H), 8.42 (s, 1H).

Example 3 3-Aminomethyl-4,6-dimethylpyridine (Cpd 2a)

An alternative route for the preparation of compound 2a is describedherein. 2-chloro-4,6-dimethylnicotinonitrile (5.0 g, 30 mmol) wasdissolved in methanol (50 mL) and the solution was carefully added to aParr reaction vessel containing 10% Pd on charcoal (500 mg) under argon.The reaction was run on Parr hydrogenation apparatus at 55 psi untiluptake of hydrogen had ceased (˜12 h). Upon completion, the catalyst wasremoved via filtration through a pad of diatomaceous earth. The pad wasrinsed with methanol (3×50 mL) and the filtrate was reduced in vacuo toprovide Compound 2a. The crude mixture was used in further synthesiswithout additional purification. MS m/z (ES)=137.1 (M+H); ¹H NMR (DMSO,d₆) δ 2.35 (s, 3H), 2.42 (s, 3H), 4.01 (s, 2H), 7.13 (s, 1H), 8.42 (s,1H).

Example 4 2-amino-3-aminomethyl-4,6-dimethylpyridine (Cpd 4a)

2-Amino-3-aminomethyl-4,6-dimethylpyridine (Cpd 4a).2-amino-3-cyano-4,6-dimethylpyridine (1.0 g, 6.8 mmol) was dissolved inethanol (35 mL) and the mixture was treated with Raney nickel (3 mL,slurry in water) and hydrazine hydrate (3.4 mL, 67.9 mmol). The solutionwas stirred overnight at room temperature. Compound 4a was obtained byfiltering the reaction mixture through a pad of diatomaceous earth,which was rinsed with methanol (3×50 mL). The filtrate was dried overNa₂SO₄, filtered and concentrated under reduced pressure to affordCompound 4a. The compound was used without additional purification.

Example 56-[(4,6-Dimethyl-pyridin-3-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 22)

A. ((4-Methoxybenzyl)amino)carbonyl)carbamimidothioic acid methyl ester(Cpd 5b). S-methylisothiouronium sulfate (15.35 g, 55.2 mmol) wasdissolved in 8:2:1 MeOH/H₂O/THF (150 mL) and the mixture was treatedwith 3 N NaOH (18.4 mL, 55.2 mmol). The solution was then cooled to 0 Cand 4-methoxybenzyl isocyanate (Cpd 5a, 9.0 g, 55.2 mmol) was addeddropwise over 30 min. The reaction was stirred overnight and graduallywarmed to room temperature. The mixture was then washed with saturatedaqueous NH₄Cl (100 mL) and extracted with dichloromethane (3×75 mL). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resultant residue was purifiedby normal phase column chromatograpy (silica gel, 20% EtOAc-100% EtOAcin heptane), to give Compound 5b.

C.5-(Methylthio)-3,7-dioxo-1-(4-methoxybenzyl)-2-oxa-4,6,8-triazanon-4-en-9-oicacid methyl ester (Cpd 5c). A solution of Compound 5b (7.9 g, 31.2 mmol)in dichloromethane (150 mL) was treated with triethylamine (5.22 mL,37.4 mmol) and the mixture was cooled to −10 C. Methyl chloroformate(4.79 mL, 62.4 mmol) was added dropwise over 15 min and the reaction wasstirred for 4 h while gradually warming to room temperature. Thesolution was then washed with saturated aqueous NH₄Cl (100 mL) andextracted with dichloromethane (3×75 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated. The resultant residuewas purified by normal phase column chromatograpy (silica gel, 5%MeOH/95% CH₂Cl₂) to afford Compound 5c.

D. 3-(4-Methoxybenzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 5d). Compound 5c (8.1 g, 26.0 mmol) was dissolved in MeOH (150 mL)and the solution was treated with NaOMe in MeOH (4.6 M, 10.1 mL, 31.2mmol) and the reaction was allowed to stir at room temperature for 1 h.A white precipitate formed upon addition of the NaOMe. The reactionmixture was diluted with 1N HCl (50 mL) and the resultant precipitatewas collected by vacuum filtration. The solid was dried under reducedpressure at 160 C over xylenes to afford Compound 5d as its HCl salt.

E.3-(4-Methoxybenzyl)-1-(4-methoxybenzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4dione (Cpd 5e). Compound 5d (4.0 g, 12.7 mmol) was dissolved in THF andwas treated with 4-methoxybenzyl alcohol (1.75 g, 12.7 mmol),triphenylphosphine (6.7 g, 25.4 mmol), and diisopropyl azodicarboxylate(2.57 g, 12.7 mmol). The reaction was allowed to stir overnight at roomtemperature. The solution was partitioned between water (100 mL) andethyl acetate (3×75 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude mixture was purified by normal phase columnchromatograpy (silica gel, 20% ethyl acetate-100% ethyl acetate inheptane) to afford Compound 5e.

F.6-[(4,6-Dimethyl-pyridin-3-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 22). Compound 5e (100 mg, 0.25 mmol) and Compound 2a (140 mg, 1.0mmol) were suspended in EtOH (2 mL) and the reaction was irradiated at160° C. for a total of 60 min in a microwave instrument. The reactionmixture was then reduced under nitrogen and the residue was purified andisolated by reverse phase HPLC to afford Compound 61. MS m/z (ES)=488.3(M+H); ¹H NMR (DMSO, d₆) δ 2.39 (s, 3H), 2.62 (s, 3H), 3.71 (s, 3H),3.74 (s, 3H), 4.53 (m, 2H), 4.82 (s, 2H), 5.08 (s, 2H), 6.88 (m, 4H),7.22 (m, 4H), 7.67 (s, 1H), 8.47 (s, 1H).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 5, the followingcompounds were prepared:

Cpd MS obs MS calc 1 513.7 513.4 2 499.6 499.4 4 478.8 479.9 5 478.8479.9 6 475.8 476.5 8 463.1 463.5 9 525.2 525.6 10 476.9 477.5 12 544.2544.6 13 543.2 543.6 20 545.1 545.6 25 554.3 554.6 35 511.2 511.5 36503.2 503.5 37 502.2 502.5 38 529.2 529.5 39 460.2 460.5 40 460.2 460.541 460.2 460.5 52 488.2 488.5 57 551.2 551.6 58 505.2 505.5 59 474.2474.5 60 476.2 476.5 62 474.2 474.5 63 473.2 473.5 64 528.2 528.5 65474.0 474.5 75 491.2 491.6 76 446.2 446.5 77 485.2 485.5 78 455.2 455.579 439.2 439.5 80 475.2 475.5 81 470.1 470.5 82 490.1 490.5 86 473.2473.5 87 529.2 529.5 88 470.1 470.5 91 517.1 517.5 92 475.2 475.5 93503.2 503.5 94 489.1 489.5 95 476.1 476.5 96 524.2 524.5 98 529.2 529.599 542.3 542.5 100 504.1 504.6 101 459.1 459.5 102 498.1 498.6 103 452.2452.6 104 489.1 489.5 105 542.3 542.5 106 488.2 488.6 116 476.2 476.5117 492.1 493.0 122 527.8 528.5 125 487.2 487.5 126 485.2 485.5 127484.2 484.5 128 500.2 500.6 129 498.1 498.6 130 497.2 497.6 131 523.2523.6 132 536.2 536.6 135 517.2 517.6 136 533.3 533.6 137 520.2 520.5138 484.2 484.5 139 497.2 497.6 140 501.1 501.6 142 514.2 514.6 149481.2 481.6 150 494.2 494.6 152 603.3 603.7 153 468.1 468.5 154 474.2474.5 155 512.2 512.6 170 484.2 484.5 171 484.2 484.5 172 497.2 497.6200 505.5 505.5 201 474.3 474.5 203 493.1 493.5 204 506.2 506.6 205493.3 493.5 206 506.3 506.6 224 483.3 483.6 231 479.0 478.9 234 473.9473.53 235 527.8 527.50 236 527.8 527.50 237 528.2 527.50 238 443.2466.54 239 469.2 468.56 241 519.03 518.57 246 590.8 590.68 247 475.2474.52 248 489.9 489.54 250 608.27 608.70 253 487.27 487.00 254 453.3452.56 255 521.26 521.45 256 459.1 458.95 257 491.09 490.51 258 508.22507.51 259 532.2 531.61 260 533.3 532.60 263 516.9 516.60 264 528.9528.61 265 559.3 558.68 266 464.15 463.46 267 473.9 473.53 271 453.16452.51 272 465.3 464.57Additional ¹H NMR Data for Compounds of Example 5

6-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-(4-methoxy-benzyl)-1-(5-methoxy-pentyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 78). ¹H NMR (DMSO, d₆) δ 1.30 (m, 2H), 1.53 (m, 4H), 3.20 (s, 3H),3.28 (t, 2H, J=6.25 Hz), 3.71 (s, 3H), 3.79 (m, 2H), 4.38 (d, 2H, J=3.88Hz), 4.80 (s, 2H), 6.86 (m, 3H), 7.23 (d, 2H, J=8.68 Hz), 7.92 (d, 1H,J=5.31 Hz), 8.18 (m, 1H).

6-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1-(1H-indol-4-ylmethyl)-3-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 155). ¹H NMR (DMSO, d₆) δ 2.33 (s, 3H), 2.35 (s, 3H), 3.71 (s, 3H),4.35 (m, 2H), 4.84 (s, 2H), 5.32 (s, 2H), 6.43 (s, 1H), 6.60 (m, 2H),6.83 (d, 2H, J=8.67 Hz), 7.01 (t, 1H, J=8.15 Hz), 7.24 (d, 2H, J=8.66Hz), 7.34 (m, 2H), 7.98 (s, 1H), 11.25 (s, 1H).

6-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-3-(4-methoxy-benzyl)-1-(5-methoxy-pentyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 224). ¹H NMR (DMSO, d₆) δ 1.25 (m, 2H), 1.47 (m, 4H), 2.37 (s, 3H),2.49 (s, 3H), 3.19 (s, 3H), 3.25 (t, 2H, J=6.31 Hz), 3.72 (s, 3H), 3.79(t, 2H, J=6.97 Hz), 4.37 (d, 2H, J=4.30 Hz), 4.80 (s, 2H), 6.69 (s, 1H),6.86 (d, 2H, J=8.73 Hz), 7.23 (d, 2H, J=8.68 Hz), 7.60 (s, 1H), 7.80 (m,1H).

Example 6

Example 6 describes an alternative route for the preparation of3-(4-methoxybenzyl)-1-(4-methoxybenzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4dione, Cpd 5e. Compound 5d (2.0 g, 7.2 mmol) was dissolved inacetonitrile (100 mL) and the reaction mixture was treated withdiisopropylethylamine (2.5 mL, 14.3 mmol) and 4-methoxybenzyl chloride(1.35 g, 8.6 mmol). The reaction mixture was then heated to 90 C and wasallowed to stir overnight. Upon cooling, the mixture was partitionedbetween saturated aqueous NH₄Cl (100 mL) and ethyl acetate (3×75 mL).Combined organic extracts were dried over Na₂SO₄, filtered and reduced.Purification by normal phase column chromatograpy (silica gel, 20% ethylacetate-100% ethyl acetate in heptane) afforded Compound 5e as a whitesolid.

Example 76-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 97)

Compound 5e (100 mg, 0.25 mmol) and Compound 4a (76 mg, 0.50 mmol) weresuspended in EtOH (2 mL) and the reaction was irradiated at 160 C for atotal of 60 minutes in a microwave instrument. The reaction mixture wasthen reduced under nitrogen and the resultant residue was purified andisolated by reverse phase HPLC to afford Compound 97. MS m/z (ES)=503.19(M+H); ¹H NMR (DMSO, d₆) δ 2.35 (s, 3H), 2.36 (s, 3H), 3.72 (s, 3H),3.73 (s, 3H), 4.36 (d, 2H, J=3.33 Hz), 4.83 (s, 2H), 4.99 (s, 2H), 6.65(s, 1H), 6.87 (m, 4H), 7.15 (d, 2H, J=8.63 Hz), 7.23 (d, 2H, J=8.61 Hz),7.62 (s, 2H), 7.97 (m, 1H).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 7, the followingcompounds were prepared:

Cpd MS obs MS calc 157 515.2 515.6 212 529.3 529.6 213 571.4 571.7

Example 83-(2,3-Dihydro-benzofuran-5-ylmethyl)-6-[(4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 123)

A. 1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 6b). To (4-methoxy-benzyl) thiourea (Cpd 8a, 2.00 g, 10.1 mmol) inMeOH (40 mL) was added methyl iodide (0.64 mL, 10.1 mmol). The reactionwas stirred at room temperature for 24 h. The reaction mixture wasconcentrated to yield crude compound 8b that was used in the next stepwithout further purification.

B. 1-(4-Methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 6c). To Compound 8b (3.6 g, 17.1 mmol) in methylene chloride (40mL) was added excess diisopropylethylamine (6.61 g, 51.3 mmol). Thereaction mixture was cooled to 0 C. A portion of N-chlorocarbonylisocyanate (1.78 g, 17.1 mmol) was added dropwise. The reaction mixturewas allowed to slowly warm to room temperature. After 24 h, water wasadded and the reaction mixture was extracted with ethyl acetate. Thephases were separated, and the organic layer was dried over sodiumsulfate, filtered, and concentrated. Methanol was added to the crudeproduct, and the solid was collected by vacuum filtration to giveCompound 8c. ¹H NMR (DMSO-d₆) δ 2.45 (3H, s), 3.73 (3H, s), 4.98 (2H,s), 6.89-6.92 (2H, d, J=8.5 Hz), 7.22-7.25 (2H, d, J=8.5 Hz), 11.58 (1H,s).

C.3-(2,3-Dihydro-benzofuran-5-ylmethyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 8d). To Cpd 8c (0.3 g, 1.07 mmol) in tetrahydrofuran was added2,3-dihydro-1-benzofuran-5-ylmethanol (0.16 g, 1.07 mmol),triphenylphosphine (0.57 g, 2.15 mmol) and diethyl azodicarboxylate(0.22 g, 1.29 mmol). The reaction was stirred at room temperature for 24h. The reaction mixture was taken up in ethyl acetate, washed withwater, and the phases were separated. The organic layer was dried oversodium sulfate, filtered, and concentrated. The resulting material waspurified by normal phase chromatography using an ISCO automated systemto give Cpd 8d.

D.3-(2,3-Dihydro-benzofuran-5-ylmethyl)-6-[(4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 8e). Compound 8d (100 mg, 0.24 mmol) and compound 3a (33 mg, 0.25mmol) were suspended in EtOH (2 mL) and the reaction was irradiated at160 C for 60 minutes in a microwave instrument. The reaction mixture wasthen reduced under nitrogen and the product was purified and isolated byreverse phase HPLC to afford Compound 123. MS m/z (ES)=500.0 (M+H); ¹HNMR (DMSO, d₆) δ 2.49 (3H, s), 2.60 (3H, s), 3.08-3.19 (2H, t, J=8.64Hz), 3.73 (3H, s), 4.45-4.53 (4H, m), 4.80 (2H, s), 5.05 (2H, s),6.65-6.68 (1H, d, J=8.18 Hz), 6.87-6.91 (1H, d, J=8.7 Hz), 7.03-7.06(1H, m), 7.15-7.18 (2H, m), 7.66 (1H, s), 8.30-8.35 (1H, br s), 8.45(1H, s).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 8, the followingcompounds were prepared:

Cpd MS obs MS calc 45 529.1 529.5 46 489.3 489.5 47 490.2 490.5 48 515.2515.6 49 513.2 513.5 55 463.2 463.5 56 503.3 503.5 107 501.9 502.6 108503.0 503.5 109 527.8 528.6 110 525.9 526.5 111 488.0 488.6 112 475.9476.5 113 458.9 459.5 114 515.8 516.6 124 519.9 520.5 133 497.9 498.6134 484.9 485.5 143 474.9 475.5 144 487.9 488.6 145 500.9 501.6 146513.9 514.6

Example 96-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-(4-hydroxy-benzyl)-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 54)

A.6-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzyl]-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 9a) (150 mg, 0.26 mmol) was prepared according to the methodsdescribed in Example 8, and substituting[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol for2,3-dihydro-1-benzofuran-5-ylmethanol in Step C.

B.6-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-(4-hydroxy-benzyl)-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 54). Compound 7a was suspended in THF (3 mL) and the reactionmixture was treated with tetrabutylammonium fluoride monohydrate (82 mg,0.31 mmol). The solution was stirred at room temperature overnight. Themixture was then concentrated under nitrogen and the residue waspurified by reverse phase HPLC to give the title compound 54. MS m/z(ES)=461.1 (M+H).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 9, the followingcompounds were prepared:

Cpd MS obs MS calc 181 510.2 510.5

Example 106-[(6-Amino-pyridin-2-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 115)

A. 2,2-Dimethyl-N-(6-methyl-pyridin-2-yl)-propionamide (Cpd 10b) To amixture of 2-amino-6-methylpyridine 10a (500 mg, 4.6 mmol), andtriethylamine (778 μL, 5.98 mmol) in dichloromethane (50 mL) was addedpivaloyal chloride (628 μL, 5.1 mmol). The mixture was allowed to stirat room temperature for three hours. The mixture was washed withsaturated sodium bicarbonate followed by brine. The organic extract wasdried over magnesium sulfate and concentrated to give Compound 10b (876mg) as a crude oil, which solidified upon standing.

B. N-(6-Bromomethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (Cpd 10c) Amixture of compound 10b, (776 mg, 4.03 mmole), N-bromosuccinimide (NBS)(431 mg, 2.4 mmol), and 2,2′-azobisisobutyronitrile (66 mg, 0.4 mmol) incarbon tetrachloride (100 mL) was heated to 90° C. for 2.5 hours. LCanalysis indicated a mixture of the desired product, undesireddi-bromonated material and starting material. The mixture was cooled toroom temperature, washed with saturated sodium bicarbonate and brine.The organic extract was dried over magnesium sulfate and concentrated toyellow oil. The oil was purified by normal phase chromatography, elutingwith 10-30% ethyl acetate in heptane to yield compound 10c. MS m/z(ES)=193.2 (M+H).

C.N-[6-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide(Cpd 10d) A mixture of compound 10c (335 mg, 1.24 mmol) and potassiumphthalamide (230 mg, 1.24 mmol) in DMF (3 mL) was heated to 160° C. inan oil bath for 4 hours. The mixture was cooled to room temperature andallowed to stir overnight. The mixture was diluted with water (100 mL)and extracted 2× with ethyl acetate. The combined organic extracts werewashed with water, dried over magnesium sulfate and concentrated to ayellow oil-solid. This material was purified by normal phasechromatography, eluting with 30-50% ethyl acetate in heptane to givecompound 10d. MS m/z (ES)=338.1 (M+H).

D. N-(6-Aminomethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (Cpd 10e). Amixture of compound 10d (200 mg, 0.59 mmol, and hydrazine monohydrate(29 μL, 0.59 mmol) in ethanol (10 mL) was heated to 90° C. for six hoursthen cooled to rt and allowed to stir overnight. LC analysis indicatedthe reaction was incomplete so an additional 5 μL of hydrazinemonohydrate was added and the mixture was heated to 90° C. for 22 h. Themixture was concentrated, and the resultant residue was taken up inethyl acetate, giving a white precipitate. The precipitate was removedby filtration, and the filtrate was concentrated and then purified byreverse phase liquid chromatography to afford Compound 10e. MS m/z(ES)=208.1 (M+H). ¹H NMR (MeOD, d₄). δ 1.25 (s, 9H), 4.12 (s, 3H), 7.18(d, 1H, J=7.7 Hz), 7.84 (t, 1H, J=8.0, 7.8 Hz), 8.01-8.04 (d, 1H, J=8.0Hz).

E. 6-Aminomethyl-pyridin-2-ylamine (Cpd 10f). To a solution of compound10e (100 mg, 0.48 mmol) in water (10 mL) was added concentrated HCl (500μL, 12M). The mixture was heated to reflux for 30 minutes. After coolingto rt, the solution was allowed to stir overnight. Nitrogen gas wasbubbled through the solution for one hour. The solution was thenlyophilized to obtain compound 10f. MS m/z (ES)=124.1 (M+H).

F.6-[(6-Amino-pyridin-2-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 115). A mixture of compound 5e (168 mg, 0.42 mmol), compound 10f(95 mg, 0.42 mmol), diisopropylethylamine (187 μL, 1.7 mmol) and ethanol(3 mL) was irradiated at 140° C. for 20 minutes in a microwaveinstrument. Subsequently, the mixture was irradiated at 160° C. for 20minutes in a microwave instrument. The resulting mixture was purified byreverse phase HPLC to give compound 115 as its TFA salt. MS m/z(ES)=474.9 (M+H). ¹H NMR (DMSO, d₆). δ 3.65 (s, 3H), 3.74 (s, 3H), 4.44(s, 2H), 4.64 (s, 2H), 5.01 (s, 2H), 6.32 (d, 1H, J=7.3 Hz), 6.71 (d,1H, J=8.7 Hz), 6.79 (d, 2H, J=8.7 Hz), 6.86 (d, 2H, J=8.7 Hz), 7.14-7.18(dd, 4H, J=5.2, 5.2 Hz), 7.72 (t, 1H, J=7.6, 8.4 Hz), 7.71-7.75 (bs,2H), 8.33 (s, 1H).

Example 111,3-Bis-(4-methoxy-benzyl)-6-[(6-propylamino-pyridin-2-ylmethyl)-amino]-1H-[1,3,5]triazine-2,4-dione,(Cpd 147)

A.1,3-Bis-(4-methoxy-benzyl)-6-[(6-propylamino-pyridin-2-ylmethyl)-amino]-1H-[1,3,5]triazine-2,4-dione(Cpd 147). A mixture of Compound 115 (30 mg, 0.13 mmol), propionaldehyde(5.8 μL, 0.086 mmol), sodium triacetoxyborohydride (18 mg, 0.086 mmol)and acetic acid (12 μL, 0.215 mmol) in dichloroethane (5 mL) was allowedto stir at room temperature. After four days, an additional 10 μL ofpropionaldehyde was added. After stirring an additional day, another 10μL of propionaldehyde as added. The reaction was washed with saturatedsodium bicarbonate and brine. The organic layer was dried over magnesiumsulfate, filtered, and the filtrate was concentrated. The concentratewas purified by reverse phase chromatography to obtain compound 147 asits TFA salt. MS m/z (ES)=516.9 (M+H).

Example 126-[(6-Amino-pyridin-2-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 148)

A. 6-Chloro-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione (Cpd10b). A solution of 6-chlorouracil 12a, (500 mg, 3.4 mmol),4-methoxybenzyl alcohol (990 mg, 7.2 mmol), triphenylphosphine (2.9 g,11.2 mmol), diisopropylazodicarboxylate (1.6 mL, 8.2 mmol) in THF (100mL) was allowed to stir at room temperature overnight. The solution wasconcentrated. The concentrate was taken up in ethyl acetate and washedwith saturated sodium bicarbonate and brine. The organic layer was driedover magnesium sulfate, filtered, and the filtrate was concentrated. Theconcentrate was purified by reverse phase chromatography to affordcompound 12b. MS m/z (ES)=386.9 (M+H). ¹H NMR (MeOD, d₄). δ 3.75 (s,3H), 3.76 (s, 3H), 5.01 (s, 2H), 5.21 (s, 2H), 5.99 (s, 1H), 6.82-6.88(dd, 4H, J=8.9, 8.9 Hz), 7.22 (d, 2H, 8.5 Hz), 7.32 (d, 2H, J=8.9 Hz).

B.6-[(6-Amino-pyridin-2-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 12c). A suspension of compound 10f, (50 mg, 0.13 mmol), compound12b (25 mg, 0.13 mmol), diisopropylethylamine (57 μL, 0.52 mmol) inethanol (3 mL) was irradiated at 140° C. for 20 minutes in a microwaveinstrument. The mixture was concentrated and the residue purified byreverse phase chromatography to obtain compound 148 as its TFA salt. MSm/z (ES)=473.9 (M+H). ¹H NMR (DMSO, d₆). δ 3.72 (s, 6H), 4.23 (bs, 2H),4.77 (s, 2H), 5.12 (s, 2H), 6.78 (d, 1H, J=9.4 Hz), 6.88 (m, 1H), 6.81(d, 2H, J=8.4 Hz), 6.91 (d, 2H, J=9.0 Hz), 7.22 (dd, 4H, J=8.9, 8.9 Hz),7.40 (t, 1H, J=5.4, 5.4 Hz), 7.72 (t, 1H, J=8.4, 7.9 Hz).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 12, thefollowing compounds were prepared:

Cpd MS obs MS calc 26 474.3 474.5 61 487.2 487.6

Example 133-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-[(5,6,7,8-tetrahydro-1,8]naphthyridin-2-ylmethyl)-amino]-1H-[1,3,5]triazine-2,4-dione(Cpd 21)

A. 2-Dimethoxymethyl-[1,8]naphthyridine (Cpd 13b). A solution of2-amino-3-pyridine carboxaldehyde (13a, 50 mg, 4.1 mmol), pyruvicaldehyde dimethyl acetal (641 μL, 5.3 mmol), 3N sodium hydroxide (1.8mL, 5.3 mmol), ethanol (50 mL) and water (5 mL) was allowed to stir atroom temperature overnight. The mixture was concentrated and the residuepartitioned between ethyl acetate and brine. The organic layer was driedover magnesium sulfate, filtered, and the filtrate was concentrated toobtain 13b.

B. 7-Dimethoxymethyl-1,2,3,4-tetrahydro-[1,8]naphthyridine (Cpd 13c). Amixture of 13b (0.8 g, 3.9 mmol) and platinum oxide (27 mg, 0.12 mmol)in ethanol (100 mL) was placed under a hydrogen atmosphere atatmospheric pressure for 22 hours. The mixture was filtered through apad of diatomaceous earth and the filtrate was concentrated to obtainproduct 13c (0.73 g) as a white solid.

C. 5,6,7,8-Tetrahydro-[1,8]naphthyridine-2-carbaldehyde (Cpd 13d).Compound 13c (0.73 g) was dissolved in trifluoroacetic acid (5 mL). Theresulting mixture was allowed to stir at room temperature under argonfor 1.5 hours. The mixture was concentrated. The residue was dissolvedin methylene chloride and washed 2× with saturated sodium bicarbonatesolution. The organic layer was dried over magnesium sulfate, filtered,and the filtrate was concentrated to obtain compound 13d.

D. 5,6,7,8-Tetrahydro-[1,8]naphthyridine-2-carbaldehyde oxime (Cpd 13e).A solution of hydroxylamine hydrochloride (0.46 g, 6.6 mmol), and sodiumacetate trihydrate (0.90 g, 6.6 mmol) in water (50 mL) was heated to 60°C. To this mixture was added dropwise, a solution of 13d (0.54 g, 3.3mmol) in methanol (50 mL). After stirring for 2 hours, the mixture wasconcentrated to approximately 50 mL. The residue was diluted withsaturated sodium sulfate and extracted 2× with ethyl ether. The combinedorganic extracts were washed with saturated sodium bicarbonate solution,dried over sodium sulfate and concentrated to obtain compound 13e.

E. C-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-methylamine (Cpd 13f).To a solution of 13e (0.46 g, 2.6 mmol) in trifluoroacetic acid (10 mL)was added zinc dust (0.95 g, 15 mmol). The mixture was stirredvigorously for 20 minutes. The resulting solution was poured into amixture of 3N sodium hydroxide (43 mL, 130 mmol), and methylene chloride(50 mL) that was cooled in an ice bath. After warming to roomtemperature, the mixture was filtered through a pad of diatomaceousearth and rinsed with additional dichloromethane and water. The phasesof the filtrate were separated. The organic layer was dried over sodiumsulfate, filtered, and concentrated obtain the compound 13f. MS m/z(ES)=164.1 (M+H). ¹H NMR (CDCl₃). δ1.56-1.82 (bs, 2H), 1.91 (q, 2H,J=6.6, 5.9, 5.5, 6.6 Hz), 2.70 (t, 2H, J=6.2, 6.2 Hz), 3.40 (m, 2H),3.71 (s, 2H), 4.84 (bs, 1H), 6.44 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2Hz).

F.3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 13g). Compound 13g was obtained using the procedure described inExample 8, Step C, substituting 4-fluorobenzyl alcohol for2,3-dihydro-1-benzofuran-5-ylmethanol.

G.3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-1H-[1,3,5]triazine-2,4-dione(Cpd 21). A mixture of 13g (50 mg, 0.13 mmol) and compound 13f (42 mg,0.26 mmol) in ethanol (2 mL) was irradiated at 140° C. in a microwaveinstrument for two 20 minute cycles. The resulting mixture wasconcentrated and purified by reverse phase chromatography to obtain thedesired compound 21. MS m/z (ES)=503.3 (M+H). ¹H NMR (DMSO-d₆). δ1.81(bs, 2H), 2.72 (bs, 2H), 3.40 (bs, 2H), 4.49 (bs, 2H), 4.88 (s, 2H),5.08 (s, 2H), 6.31-6.34 (d, 2H, J=7.3 Hz), 6.94 (d, 2H, J=8.7 Hz),7.10-7.23 (m, 4H), 7.31-7.36 (m, 2H), 7.52 (d, 1H, J=7.3 Hz), 7.99 (bs,1H), 8.40 (bs, 1H).

Example 141,3-Bis-(4-methoxy-benzyl)-6-(pyridin-3-ylmethoxy)-1H-pyrimidine-2,4-dione(Cpd 121)

A solution of 12b (50 mg, 0.13 mmol) in dichloromethane (3 mL) was addedto a mixture of pyridine 3-methanol (25 μL, 0.26 mmol),benzyltriethylammonium chloride (3 mg, 0.13 mmol) in 1N sodium hydroxidesolution (2.6 mL). After stirring at room temperature for 24 hours, anadditional 100 μL of pyridine 3-methanol was added. After stirring anadditional 24 hours, the reaction mixture was separated, the organiclayer dried over magnesium sulfate, filtered, and the filtrate wasconcentrated. The concentrate was purified by reverse phasechromatography to obtain Compound 121. MS m/z (ES)=459.9 (M+H). ¹H NMR(DMSO-d₆). δ 3.71 (s, 6H), 4.92 (d, 4H, J=7.8 Hz), 5.29 (s, 2H), 5.45(s, 1H), 6.84 (t, 4H, J=8.73, 8.91), 7.09 (d, 2H, J=8.74 Hz), 7.23 (d,2H, J=8.61 Hz), 7.55 (q, 1H, J=5.04, 2.77, 5.07 Hz), 7.86 (d, 1H, J=7.99Hz), 8.63 (s, 2H).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 14, thefollowing compounds were prepared:

Cpd MS obs MS calc 190 474.9 475.5 202 503.3 503.6 225 488.9 489.5 232476.2 475.5

Example 15 (3-Aminomethyl-pyridin-2-yl)-(2-methoxy-ethyl)-amine (Cpd15c)

A. 2-(2-Methoxy-ethylamino)-nicotinonitrile (Cpd 15b) To a solution of3-cyano-2-fluoropyridine (15a) (100 mg, 0.82 mmol) in tetrahydrofuran(1.6 mL) was added cesium carbonate (267 mg, 0.82 mmol) and2-methoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at roomtemperature for 18 h, and then concentrated. The residue was taken up indichloromethane/water, absorbed onto diatomaceous earth, and eluted withdichloromethane. The eluate was concentrated to provide compound 15b.

B. (3-Aminomethyl-pyridin-2-yl)-(2-methoxy-ethyl)-amine (Cpd 15c) To acooled (0° C.) solution of lithium aluminum hydride (0.82 mL, 1Msolution in tetrahydrofuran, 0.82 mmol) was added compound 15b intetrahydrofuran (1 mL). The reaction mixture was stirred at 0° C. for 15min, then stirred at room temperature for 1 h. After successivelyquenching with water (0.15 mL), sodium hydroxide (0.15 mL, 2N solutionin water), and water (0.15 mL) the mixture was filtered and concentratedto furnish compound 15c.

Example 163-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-{[2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl]-amino}-1H-[1,3,5]triazine-2,4-dione(Cpd 28)

To a reaction vessel containing compound 13g (40 mg, 0.1 mmol) inethanol (0.75 mL) was added compound 15c (36 mg, 0.2 mmol). The mixturewas irradiated at 180° C. in a microwave instrument for two 30 minintervals, then concentrated. The residue was dissolved in methylsulfoxide and purified by reverse phase chromatography to furnish thetitle compound 28 as its trifluoroacetate salt. ¹H NMR (methanol-d₄): δ7.78 (d, 1H, J=4.9 Hz), 7.68 (d, 1H, J=5.8 Hz), 7.46 (m, 2H), 7.12 (d,2H, J=8.7 Hz), 7.02 (t, 2H, J=8.8 Hz), 6.85-6.80 (m, 3H), 5.10 (s, 2H),5.03 (s, 2H), 4.57 (s, 2H), 3.75 (s, 3H), 3.59 (m, 4H), 3.19 (s, 3H);HRMS m/z (M+H)⁺ calcd for C₂₇H₃₀FN₆O₄ 521.2313, found 521.2302.

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 16, thefollowing compounds were prepared:

Cpd MS obs MS calc 11 517.1 517.6 15 505.2 505.6 17 533.2 533.6 18 549.2549.6 19 491.2 491.5 27 534.2 534.6 29 507.2 507.5 30 506.1 506.6 31545.1 545.6 34 517.3 517.6 50 533.2 533.6 51 546.2 546.6 66 549.2 549.767 545.3 545.7 68 559.1 559.6 69 555.1 555.6 70 586.2 586.7 71 517.2517.6 72 533.0 533.6 73 561.2 561.6 74 562.2 562.6

Example 176-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-[2-(4-fluoro-phenoxy)-ethyl]-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 141)

A.3-[2-(4-Fluoro-phenoxy)-ethyl]-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 17a). To a reaction vessel containing compound 8c (28 mg, 0.1 mmol)in acetonitrile (0.5 mL) was added cesium carbonate (32 mg, 0.1 mmol)and 1-(2-bromo-ethoxy)-4-fluoro-benzene (17.1 mg, 0.1 mmol). The mixturewas stirred at room temperature for 16 h, then concentrated. The residuewas taken up in dichloromethane/water, absorbed onto diatomaceous earth,and eluted with dichloromethane. The eluate was concentrated to providecompound 17a.

B.6-[(2-Amino-pyridin-3-ylmethyl)-amino]-3-[2-(4-fluoro-phenoxy)-ethyl]-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 141). To Compound 17a in ethanol (0.5 mL) was added Compound 1a (18mg, 0.15 mmol). The mixture was irradiated at 180° C. in a microwaveinstrument for two 30 min intervals, then concentrated. The residue wasdissolved in methyl sulfoxide and purified by reverse phasechromatography to furnish the title compound 141 as its trifluoroacetatesalt. ¹H NMR (methanol-d₄): δ 7.80 (d, 1H, J=4.8 Hz), 7.61 (d, 1H, J=5.8Hz), 7.17 (s, 1H), 7.14 (s, 1H), 6.98-6.79 (m, 8H), 5.12 (s, 2H), 4.50(s, 2H), 4.28 (m, 2H), 4.22 (m, 2H), 3.77 (s, 3H); HRMS m/z (M+H)⁺ calcdfor C₂₅H₂₆FN₆O₄ 493.2000, found 493.1999.

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 17, thefollowing compounds were prepared:

Cpd MS obs MS calc 23 485.1 485.5 24 491.1 491.6 42 475.2 475.5 43 445.2445.5 44 470.1 470.5 60 476.2 476.5 83 524.0 524.5 84 510.9 511.5 89571.1 571.4 90 511.1 511.6 119 498.2 498.6 120 503.0 503.5 156 499.2499.5 197 468.2 468.6 207 502.2 502.5 209 516.3 516.6 216 513.2 513.6217 516.1 516.6 218 506.2 506.6 220 517.1 517.6 222 528.2 528.6 229497.2 497.6 230 484.2 484.5Additional ¹H NMR Data for Compounds of Example 17

6-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1-(4-methoxy-benzyl)-3-(1-methyl-1H-benzotriazol-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 222). ¹H NMR (methanol-d₄): δ 7.97 (s, 1H), 7.70 (m, 2H), 7.32 (d,1H, J=8.7 Hz), 7.08 (d, 1H, J=8.7 Hz), 6.84 (m, 2H), 6.61 (s, 1H), 5.23(s, 2H), 5.14 (s, 2H), 4.51 (s, 2H), 4.32 (s, 3H), 3.75 (s, 3H), 2.40(s, 3H), 2.26 (s, 3H); HRMS m/z (M+H)⁺ calcd for C₂₇H₃₀N₉O₃ 528.2472,found 517.2468.

Example 181-(4-Difluoromethoxy-benzyl)-6-[(4,6-dimethyl-pyridin-3-ylmethyl)-amino]-3-(4-fluoro-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 160)

A. (4-Difluoromethoxy-benzyl)-thiourea (18b). To a solution of compound18a (2.0 g, 11.6 mmol) in dichloromethane (12 mL) at −78° C. was addedethereal hydrogen chloride (24 mL, 1.0 M solution in ethyl ether, 24mmol). The mixture was allowed to warm to room temperature, thenconcentrated. To the resulting residue in 1,4-dioxane (32 mL) was addedpotassium isothiocyanate (1.7 g, 17.3 mmol). The mixture was stirred atreflux for 16 h, then concentrated. The residue was taken up intetrahydrofuran (25 mL), poured into water (50 mL), and the layersseparated. The aqueous layer was extracted with ethyl acetate (3×) andthe combined organic layer was washed with 1N HCl and brine. The organiclayer was dried over magnesium sulfate, filtered, and the filtrate wasconcentrated to provide compound 18b.

B. (4-Difluoromethoxy-benzyl)-thiourea hydroiodide (Cpd 18c). A mixtureof Compound 18b (2.44 g, 10.5 mmol), iodomethane (1.8 g, 12.6 mmol), andmethanol (13 mL) was stirred at room temperature for 18 h, thenconcentrated to a residue to provide Compound 18c, which was usedwithout further purification in subsequent reactions.

C. 1-(4-Difluoromethoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine2,4-dione (Cpd 18d). To compound 18c in tetrahydrofuran (35 mL) wasadded cesium carbonate (17.1 g, 52.5 mmol). After cooling the mixture to0° C., N-chloro-carbonyl isocyanate (4.4 g, 42 mmol) was added and thereaction mixture was stirred vigorously for 18 h, then concentrated. Theresulting residue was taken up in dichloromethane and water and thelayer was separated. The aqueous layer was extracted withdichloromethane and the combined organic layers were concentrated. Theresultant residue was purified by flash chromatography (0-30%methanol/dichloromethane) to provide Compound 18d.

D.1-(4-Difluoromethoxy-benzyl)-3-(4-fluoro-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione(Cpd 18e). To a reaction vessel containing compound 18d (31 mg, 0.1mmol) in acetonitrile (0.5 mL) was added cesium carbonate (32 mg, 0.1mmol) and 4-fluorobenzyl bromide (18.9 mg, 0.1 mmol). The mixture wasstirred at room temperature for 18 h, then concentrated. The residue wastaken up in dichloromethane/water, absorbed onto diatomaceous earth, andeluted with dichloromethane. The eluate was concentrated to provideCompound 18e.

E.1-(4-Difluoromethoxy-benzyl)-6-[(4,6-dimethyl-pyridin-3-ylmethyl)-amino]-3-(4-fluoro-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 160) To compound 18e in ethanol (0.5 mL) was added compound 2a (16mg, 0.12 mmol). The mixture was irradiated at 180° C. in a microwaveinstrument for two 30 min intervals, then concentrated. The residue wasdissolved in methyl sulfoxide and purified by reversed-phasechromatography to furnish the title compound 160 as its trifluoroacetatesalt. ¹H NMR (methanol-d₄): δ 8.49 (s, 1H), 7.64 (s, 1H), 7.41 (m, 2H),7.23 (d, 2H, J=8.7 Hz), 7.12 (d, 2H, J=8.6 Hz), 7.00 (t, 2H, J=8.8 Hz),6.82 (t, 1H, ²J_(HF)=73.8 Hz), 5.19 (s, 2H), 4.99 (s, 2H), 4.61 (s, 2H),2.67 (s, 3H), 2.38 (s, 3H); HRMS m/z (M+H)⁺ calcd for C₂₆H₂₅F₃N₅O₃512.1909, found 512.1911.

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 18, thefollowing compounds were prepared:

Cpd MS obs MS calc 85 545.8 546.5 158 560.3 560.6 159 620.2 620.4 161508.2 508.5 162 562.1 562.5 163 560.1 560.5 164 519.2 519.5 165 552.2552.6 166 524.5 524.5 167 542.5 542.5 168 578.2 578.6 173 555.2 555.6174 565.2 565.6 175 549.2 549.6 176 551.2 551.6 177 540.2 540.6 178534.2 534.5 179 536.3 536.6 180 519.2 519.5 182 552.2 552.6 185 527.2527.6 186 525.1 525.6 191 524.2 524.5 192 549.2 549.6 193 524.3 524.5194 537.4 537.5 195 560.3 560.5 196 552.2 552.6 198 504.4 504.6 208538.1 538.5 210 552.2 552.6 219 553.1 553.5 221 564.2 564.6 227 533.2533.6 228 520.0 520.5 242 515.1 514.57 243 528.13 527.61 244 512.36511.55 245 525.23 524.58 268 512.22 511.49Additional ¹H NMR Data for Compounds of Example 18

6-[(2-Amino-pyridin-3-ylmethyl)-amino]-1-(4-difluoromethoxy-benzyl)-3-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 35). ¹H NMR (DMSO, d₆) δ 3.65 (s, 3H), 4.27 (d, 2H, J=5.03 Hz),4.76 (s, 2H), 5.04 (s, 2H), 6.80 (m, 4H), 7.16 (m, 4H), 7.27 (d, 2H,J=8.72 Hz), 7.83 (d, 1H, J=6.07 Hz), 8.18 (m, 1H).

6-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1,3-bis-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 185). ¹H NMR (DMSO, d₆) δ 2.36 (s, 3H), 2.37 (s, 3H), 3.10 (td, 4H,J=5.72, 3.59 Hz), 4.36 (m, 2H), 4.49 (td, 4H, J=5.05, 3.55 Hz), 4.81 (s,2H), 5.00 (s, 2H), 6.65 (s, 1H), 6.68 (d, 2H, J=8.19 Hz), 7.01 (m, 4H),7.50 (s, 1H), 8.01 (s, 1H).

Example 19 C-Imidazo[1,2-a]pyridin-8-yl-methylamine (Cpd 17c)

A. Imidazo[1,2-a]pyridine-8-carbonitrile (Cpd 19b). To a solution of2-amino-3-cyanopyridine (Cpd 19a) (1.0 g, 8.4 mmol) in ethanol (20 mL)was added chloroacetaldehyde (1.57 g, 50 wt. % solution in water, 10.0mmol). The mixture was irradiated at 120° C. in a microwave instrumentfor 30 min. After quenching with saturated aqueous sodium carbonate, themixture was concentrated. The residue was taken up indichloromethane/water and the layers were separated. The aqueous layerwas extracted with dichloromethane (2×) and the combined organic layerwas washed with brine, dried over MgSO₄, filtered, and the filtrate wasconcentrated to provide compound 19b.

B. C-Imidazo[1,2-a]pyridin-8-yl-methylamine (Cpd 19c). A mixture ofcompound 19b (413 mg, 2.88 mmol), palladium (100 mg, 10 wt. % supportactivated carbon), and ammonia (40 mL, 2M solution in methanol) washydrogenated at 55 psi pressure for 18 h at room temperature. Thereaction mixture was filtered through a pad of diatomaceous earth andwashed with methanol. The filtrate was concentrated to provide compound19c, which was used in subsequent reactions without furtherpurification.

Example 206-[(Imidazo[1,2-a]pyridin-8-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 188)

A solution of compound 5e (60 mg, 0.15 mmol) and compound 19c (26 mg,0.18 mmol) in ethanol (0.5 mL) was irradiated at 180° C. in a microwaveinstrument for two 30 min intervals, then concentrated. The residue wasdissolved in methyl sulfoxide and purified by reversed-phasechromatography to furnish the title compound 188 as its trifluoroacetatesalt. ¹H NMR (methanol-d₄): δ 8.66 (d, 1H, J=6.8 Hz), 8.20 (d, 1H, J=2.2Hz), 8.01 (d, 1H, J=2.2 Hz), 7.46 (d, 1H, J=7.4 Hz), 7.33 (d, 2H, J=8.6Hz), 7.28 (t, 1H, J=7.0 Hz), 7.15 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.8Hz), 6.83 (d, 2H, J=8.8 Hz), 5.15 (s, 2H), 4.96 (s, 2H), 4.88 (s, 2H),3.78 (s, 3H), 3.75 (s, 3H); HRMS m/z (M+H)⁺ calcd for C₂₇H₂₇N₆O₄499.2094, found 499.2052.

Example 21 3-Ethynyl-2-nitro-pyridine (Cpd 21c)

A. 2-Nitro-3-trimethylsilanylethynyl-pyridine (Cpd 21b). Compound 21a(500 mg, 2.5 mmol) and TMS-acetylene (500 μL) were dissolved in amixture of dry THF/triethylamine (10 mL/2 mL) under a nitrogenatmosphere. Pd(PPh₃)₄ (70 mg) was added as one portion, followed by ofcopper (I) iodide (50 mg). The stirred solution was kept overnight at RTand evaporated. The residue was subjected to normal phase columnchromatography (silica gel, heptane/EtOAc 2:1), providing compound 21b.¹H NMR (CDCl₃) δ 0.27 (s, 9H), 7.57 (dd, 1H, J=7.83 and 4.69 Hz), 8.06(dd, 1H, J=7.86 and 1.70 Hz), 8.48 (dd, 1H, J=4.66 and 1.69 Hz).

B. 3-Ethynyl-2-nitro pyridine (Cpd 21c) Compound 21b was dissolved indry THF (10 mL) at RT and 1 M TBAF in THF (1 mL) was added dropwise over10 min. The reaction mixture was kept at RT for 1 h, evaporated,dissolved in EtOAc/heptane (1/1 mixture) and filtered through a silicagel plug. After evaporation, compound 21c was obtained and used in thenext step without further purification.

Example 226-[2-(2-Amino-pyridin-3-yl)-ethyl]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 199)

A. 6-Iodo-1H-pyrimidine-2,4-dione (Cpd 22a) Compound 12a (5-g, 34 mmol)and sodium iodide (20 g) were dissolved in anhydrous DMF (50 mL) andheated to reflux for 1.5 h (Ar atmosphere). The DMF was evaporated, andthe solid residue dissolved in H₂O (200 mL). The solution was stirred atRT for 4 h, a solid material was collected by vacuum filtration, and thesolid was washed with H₂O and dried. The solid was crystallized fromEtOAc, providing compound 22a. ¹H NMR (DMSO-d₆) δ 6.03 (s, 1H), 11.2 (s,1H), 11.6 (s, 1H).

B. 6-Iodo-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione (Cpd 22b).Compound 22a (1.00 g, 4.2 mmol), 4-methoxybenzyl alcohol (1.7 g, 3 eq),PPh₃ (4.00 g) were dissolved in dry THF (25 mL) under an atmosphere ofN₂. DIAD was added dropwise at approximately 1 mL/min until the yellowcolor remained (about 4 eq total). The reaction mixture was stirred for4 h at RT and evaporated. The residue was subjected to normal phasecolumn chromatography (silica gel, gradient mixture heptane-ethylacetate), providing compound 22b. ¹H NMR (CDCl₃) δ 3.78 (s, 3H), 3.79(s, 3H), 5.04 (s, 2H), 5.27 (s, 2H), 6.54 (s, 1H), 6.82 (d, J=7.3 Hz,2H), 6.86 (d, J=8.7 Hz, 2H), 7.22 (d, J=7.3 Hz, 2H), 7.42 (d, J=8.7 Hz,2H). MS m/z (ES) 479.1 (M+H).

C.1,3-Bis-(4-methoxy-benzyl)-6-(2-nitro-pyridin-3-ylethynyl)-1H-pyrimidine-2,4-dione(Cpd 22c) Compound 22b (240 mg, 0.5 mmol) and compound 21c (150 mg, 1mmol) were dissolved in a mixture of dry THF (10 mL) and Et₃N (2 mL).Pd(PPh₃)₄ (40 mg) and copper (I) iodide (20 mg) were addedsimultaneously in one portion. The reaction mixture was stirredovernight at RT under a N₂ atmosphere and evaporated. The residue wassubjected to normal phase column chromatography (silica gel column,EtOAc), providing compound 22c. ¹H NMR (CDCl₃) δ 3.76 (s, 3H), 3.78 (s,3H), 5.06 (s, 2H), 5.23 (s, 2H), 6.17 (s, 1H), 6.82 (d, J=8.6 Hz), 7.27(d, J=6.4 Hz, 2H) 7.44 (dd, J=6.7 and 2.02 Hz, 2H), 7.68 (dd, J=7.8 and4.6 Hz, 1H), 8.06 (dd, J=7.8 and 1.7 Hz, 1H), 8.63 (dd, J=4.7 and 1.7Hz, 1H).

D.6-[2-(2-Amino-pyridin-3-yl)-ethyl]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 199). Compound 22c (100 mg, 0.2 mmol) was dissolved in EtOH (10 mL)and suspended with 10% Pd on carbon (40 mg). The reaction mixture washydrogenated for 24 h at RT under atmospheric pressure, filtered througha Celite plug, and evaporated. The residual material was purified byreverse phase HPLC chromatography (water/acetonitrile gradient), andthen lyophilized, to provide compound 199. ¹H NMR (DMSO-d₆) δ 2.8 (m,4H), 3.43 (s, 6H), 4.96 (s, 2H), 5.11 (s, 2H), 5.82 (s, 1H), 6.88 (m,4H), 7.15 (m, 2H), 7.24 (m, 2H), 7.77 (m, 1H), 7.86 (m, 1H), 7.92 (m,1H). MS m/z (ES) 473.2 (M+H).

Using an adaptation of the methods described in Example 22, compound 169was prepared from compound 22i, substituting 3-ethynyl pyridine forcompound 21c of Example 22, Step C.

Cpd 22i: ¹H NMR (DMSO-d₆) δ 3.71 (s, 3H), 3.72 (s, 3H), 4.95 (s, 2H),5.19 (s, 2H), 6.27 (s, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.89 (d, J=7.7 Hz,2H), 7.28 (m, 4H), 7.52 (m, 1H), 8.1 (m, 1H), 8.8 (m, 2H).

Cpd 169: ¹H NMR (DMSO-d₆) δ 2.88 (m, 2H), 2.95 (m, 2H), 3.72 (s, 6H),4.94 (s, 2H), 5.11 (s, 2H), 5.72 (s, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.89(d, J=7.6 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.79(m, 1H), 8.20 (m, 1H), 8.71 (m, 2H).

Using an adaptation of the methods described in Example 22, compound 187was prepared from compound 22k, substituting 2-ethynyl pyridine forcompound 21c of Example 22, Step C.

Cpd 22k: ¹H NMR (DMSO-d₆) δ 3.71 (s, 3H), 3.72 (s, 3H), 4.95 (s, 2H),5.17 (s, 2H), 6.29 (s, 1H), 6.89 (m, 4H), 7.26 (d, J=8.6 Hz, 2H), 7.32(d, J=8.6 Hz, 2H), 7.54 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.92 (m, 1H),8.7 (m, 1H).

Cpd 187: ¹H NMR (DMSO-d₆) δ 2.92 (m, 2H), 3.10 (m, 2H), 3.72 (s, 6H),4.93 (s, 2H), 5.10 (s, 2H), 5.66 (s, 1H), 6.88 (m, 4H), 7.11 (d, J=8.6Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 7.50 (m, 2H), 8.01 (m, 1H), 8.61 (d,J=4.49 Hz, 1H).

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 22, thefollowing compounds were prepared:

Cpd MS obs MS calc 169 458.0 458.5 183 457.9 458.5 187 458.1 458.5 189500.9 501.6 199 473.2 473.5 214 472.8 473.5

Example 236-[(2-Amino-4,6-dimethyl-1-oxy-pyridin-3-ylmethyl)-amino]-1-(4-difluoromethoxy-benzyl)-3-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 233)

A. Compound 176 (50 mg, 0.09 mmol) was prepared from compound 18d usingthe method described in Example 5, substituting2,3-dihydrobenzofuran-5-yl methanol for 4-methoxybenzyl alcohol in StepE; and substituting 2-amino-3-aminomethyl-4,6-dimethylpyridine forCompound 2a in Step F.

B.6-[(2-Amino-4,6-dimethyl-1-oxy-pyridin-3-ylmethyl)-amino]-1-(4-difluoromethoxy-benzyl)-3-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 233). Compound 176 and urea-hydrogen peroxide addition complex (200mg) were combined and the mixture was heated to 85 C. After 4 hours, themixture was dissolved in methanol (3 mL) and the temperature was reducedto 70 C. After stirring overnight, the mixture was allowed to cool andwas poured over H₂O (15 mL). The reaction was diluted with water,extracted with ethyl acetate (3×10 mL) and the combined extracts weredried over Na₂SO₄, filtered and reduced. Purification by reverse-phaseprep HPLC afforded Cpd 233. MS m/z (ES)=566.8 (M+H); ¹H NMR (DMSO, d₆) δ2.29 (s, 3H), 2.38 (s, 3H), 3.11 (t, 2H, J=8.49 Hz), 4.40 (m, 2H), 4.48(t, 2H, J=8.72 Hz), 4.80 (s, 2H), 5.04 (s, 2H), 6.68 (d, 2H, J=4.64 Hz),7.15 (m, 4H), 7.20 (s, 1H), 7.25 (d, 2H, J=8.57 Hz).

Example 246-[(2-Amino-4,6-dimethyl-1-oxy-pyridin-3-ylmethyl)-amino]-1,3-bis-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 226)

A. Compound 24a was prepared by the methods described in Example 18,Steps A through C, substituting 2,3-dihydrobenzofuran-5-yl methyl aminefor 4-difluoromethoxybenzyl amine in Step A.

B. Compound 185 (40 mg, 0.08 mmol) was prepared from compound 24a usingthe method described in Example 5, substituting2,3-dihydrobenzofuran-5-yl methanol for 4-methoxybenzyl alcohol in StepE; and substituting 2-amino-3-aminomethyl-4,6-dimethylpyridine forCompound 2a in Step F.

C.6-[(2-Amino-4,6-dimethyl-1-oxy-pyridin-3-ylmethyl)-amino]-1,3-bis-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 226). A solution of compound 185 in dichloromethane (4 mL) wastreated with m-CPBA (72%, 30 mg, 0.15 mmol) and the mixture was stirredovernight at room temperature. The reaction was then poured over 10%Na₂S₂O₄ and the organic phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers were then washed with saturated NaHCO₃ (3×10 mL)and were again extracted with dichloromethane (3×5 mL). The organicextracts were then combined and dried over Na₂SO₄, filtered, andreduced. Purification via reverse phase HPLC afforded Cpd 226 as its TFAsalt. The resulting TFA salt was taken up in dichloromethane (5 mL) andwas washed with saturated NaHCO₃ (3×5 mL). Combined organic extractswere dried over Na₂SO₄, filtered and reduced to afford Compound 226 asits free-base. M⁺ (ES⁺)=543.34.

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 24, thefollowing compounds were prepared:

Cpd MS obs MS calc 32 491.2 491.5 53 476.2 476.5 118 504.2 504.6 269488.19 487.52

Example 256-[2-(6-Amino-pyridin-2-yl)-ethyl]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 223)

A. 6-Bromo-2-trifluoroacetamido-pyridine (Cpd 25a).2-Amino-6-bromopyridine (800 mg) was dissolved in a mixture of DCM (30mL) and TEA (2 mL), and the solution was cooled in an ice bath.Trifluoroacetic anhydride (2 mL) was added by 100 μL portions. Thereaction mixture was allowed to warm up to room temperature, and thenwas washed sequentially with water and 10% sodium bicarbonate solution.The mixture was dried, filtered, and the filtrate was evaporated. Theresidue was subjected to normal phase column chromatography (silica gel,heptane/ethyl acetate 1:1), providing compound 25a. ¹H NMR (CDCl₃) δ8.65 (broad s, 1H), 8.15 (d. J=8.2 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.37(d, J=8.1 Hz, 1H).

B. 2,2,2-Trifluoro-N-(6-trimethylsilanylethynyl-pyridin-2-yl)-acetamide(Cpd 25b) Compound 25b was prepared using the methods described inExample 21, Step A. ¹H NMR (CDCl₃) δ 8.57 (broad s, 1H), 7.96 (d, J=8.3Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 0.09 (s, 9H).

C. N-(6-Ethynyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide (Cpd 25c).Compound 25c was prepared using the methods described in Example 21,Step B, substituting compound 25b for compound 21b. Purification wasachieved by normal phase column chromatography (silica gel,heptane/ethyl acetate 2:1). ¹H NMR (CDCl₃) δ 8.62 (broad s, 1H), 8.20(d, J=8.3 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 3.21(s, 1H).

D.N-{6-[1,3-Bis-(4-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-ylethynyl]-pyridin-2-yl}-2,2,2-trifluoro-acetamide(Cpd 25d). Compound 25d was prepared using the methods described inExample 22, Step C, substituting compound 25c for compound 21c.Purification was achieved by reverse phase HPLC. MS m/z 565.2 (M+H).

E.6-(6-Amino-pyridin-2-ylethynyl)-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 25e). Compound 25d (550 mg) was dissolved in EtOH (5 mL), and asaturated solution of NaHCO₃ (5 mL) was added. After stirring for 1 h atroom temperature, the reaction mixture was concentrated under reducedpressure, and the resultant residue was subjected to reverse phase HPLCand subsequent lyophilization to afford compound 25e.

F.6-[2-(6-Amino-pyridin-2-yl)-ethyl]-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 223). Compound 223 was prepared using the methods described inExample 22, Step D, substituting compound 25e for compound 22c.Purification was achieved by reverse phase HPLC followed bylyophilization. MS m/z (ES) 470.9 (M+H).

Example 261,3-Bis-(4-methoxy-benzyl)-6-(2-pyridin-4-yl-vinyl)-1H-pyrimidine-2,4-dione(Cpd 184)

Compound 26a was prepared using the methods described in Example 22,Step C, substituting 4-ethynylpyridine for compound 21c. Compound 26a(100 mg, TFA salt) was suspended with Pd on BaSO₄ (5%, 40 mg) in EtOH(20 mL). The reaction mixture was hydrogenated for 3 h at RT andatmospheric pressure, filtered through a pad of diatomaceous earth andconcentrated under reduced pressure. The residual material was purifiedby HPLC, followed by lyophilization to give compound 184. MS m/z (ES)455.9 (M+H).

Example 276-[(2-Amino-pyridin-3-ylmethyl)-amino]-1-(4-hydroxy-benzyl)-3-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 33)

A. Compound 27a (80 mg, 0.14 mmol) was prepared according to the methodsdescribed in Example 2, and substituting[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol for 4-methoxybenzylalcohol in Step D.

B.6-[(2-Amino-pyridin-3-ylmethyl)-amino]-1-(4-hydroxy-benzyl)-3-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 33). Compound 27a was suspended in THF (3 mL) and the reactionmixture was treated with tetrabutylammonium fluoride monohydrate (36 mg,0.14 mmol). The solution was stirred at room temperature overnight. Themixture was then concentrated under nitrogen and the residue waspurified by reverse phase HPLC to give the title compound 33. MS m/z(ES)=461.2 (M+H); ¹H NMR (DMSO, d₆) δ 3.72 (s, 3H), 4.33 (m, 2H), 4.83(s, 2H), 5.01 (s, 2H), 6.75 (m, 3H), 6.84 (d, 2H, J=8.71 Hz), 7.08 (d,2H, J=8.56 Hz), 7.24 (d, 2H, J=8.63 Hz), 7.46 (d, 1H, J=8.06 Hz), 7.89(d, 1H, J=4.88 Hz).

Example 286-{[(2-Amino-pyridin-3-ylmethyl)-amino]-methyl}-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 7)

A. 6-Chloromethyl-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 28a). 6-Chloromethyl uracil (500 mg, 3.1 mmol) was dissolved in THF(50 mL) and the solution was treated with 4-methoxybenzyl alcohol (860mg, 6.2 mmol), triphenylphosphine (2.45 g, 9.3 mmol) anddiisopropylazodicarboxylate (1.26 g, 6.2 mmol). The reaction was allowedto stir overnight at room temperature. The mixture was then poured overwater (75 mL) and was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered and reduced.Compound 28a was isolated and purified by normal phase columnchromatograpy (silica gel, 20% EtOAc/heptane-100% EtOAc/heptane). M⁺(ES⁺)=401.1.

B.6-{[(2-Amino-pyridin-3-ylmethyl)-amino]-methyl}-1,3-bis-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione(Cpd 7). Cpd 28a (100 mg, 0.25 mmol) was dissolved in acetonitrile (5mL) and the reaction mixture was treated with diisopropylethylamine(0.087 mL, 0.50 mmol), and 2-amino-3-methylaminopyridine (Cpd 1a) (31mg, 0.25 mmol). The solution was heated to 80 C and was allowed to stirfor 4 hours. The mixture was then cooled to room temperature and waspoured over saturated NH₄Cl (15 mL). The desired product was extractedwith ethyl acetate (3×10 mL) and the combined organic extracts weredried over Na₂SO₄, filtered and reduced. Purification and isolation byreverse phase HPLC gave compound 7. MS m/z (ES)=488.1 (M+H); ¹H NMR(DMSO, d₆) δ 2.83 (s, 2H), 3.02 (s, 2H), 4.07 (s, 6H), 4.26 (s, 2H),4.34 (s, 2H), 5.24 (s, 1H), 6.05 (m, 5H), 6.20 (d, 2H, J=6.99 Hz), 6.54(d, 2H, J=7.05 Hz), 6.92 (t, 2H, J=7.71 Hz).

Example 296-[(2-Amino-pyridin-3-ylmethyl)-amino]-1,3-bis-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 3)

Cpd 5e (850 mg, 2.1 mmol) and Cpd 1a (524 mg, 4.3 mmol) were suspendedin ethanol (10 mL) and the reaction mixture was irradiated at 160 C for100 minutes in a microwave instrument. The solution was reduced in vacuoand purified by reverse phase HPLC to afford the title compound 3. MSm/z (ES)=475.2 (M+H), ¹H NMR (DMSO, d₆) δ 3.71 (s, 3H), 3.74 (s, 3H),4.36 (d, 2H, J=4.59 Hz), 4.83 (s, 2H), 5.09 (s, 2H), 6.90 (m, 4H), 7.24(d, 4H, J=8.64 Hz), 7.57 (d, 1H, J=7.08 Hz), 7.91 (d, 1H, J=6.39 Hz),8.08 (s, 2H), 8.45 (m, 1H).

Example 30 Pyridin-3-yl-methanthiol (Cpd 30a)

Pyridin-3-yl-methanthiol (Cpd 30a). To a mixture of3-(bromomethyl)pyridine hydrobromide (500 mg, 2.0 mmol) anddiisopropylethylamine (0.220 mL, 2.0 mmol) in THF (20 mL), cooled in asodium chloride/ice bath (−5 C), was added hexamethyldisilathiane (0.500mL, 2.4 mmol) and tetrabutylammonium fluoride (575 mg, 2.2 mmol). Theresulting mixture was allowed to warm to room temperature and stirredovernight. The mixture was then concentrated and the residue partitionedbetween ethyl acetate and saturated aqueous ammonium chloride. Theorganic layer was separated, dried over MgSO₄ and concentrated. Theconcentrate was purified by normal phase chromatography, eluting withethyl acetate to obtain compound 30a. ¹H NMR (MeOD, d₄) δ 3.77 (s, 2H),7.38-7.41 (m, 1H), 7.84-7.86 (d, 1H, J=7.96), 8.38-8.40 (m, 1H), 8.50(s, 1H).

Example 311,3-Bis-(4-methoxy-benzyl)-6-(pyridin-3-ylmethylsulfanyl)-1H-pyrimidine-2,4-dione(Cpd 211)

A solution of Compound 12b (97 mg, 0.25 mmol), Compound 30a (61 mg, 0.49mmol), NaOH (3M, 1.67 mL, 5 mmol), and TEBA (6 mg, 0.025 mmol) in 2 mLof dichloromethane, was stirred vigorously overnight at roomtemperature. After 24 hours, an additional amount of Compound 12b wasadded (50 mg) and the mixture allowed to stir for a second night. Themixture was then separated, the organic layer was dried over MgSO₄,filtered, and the filtrate was concentrated. The concentrate waspurified by reverse phase chromatography to obtain compound 211. MS m/z(ES)=475.8 (M+H). ¹H NMR (DMSO, d₆). δ 3.72-3.73 (d, 6H, J=3.8 Hz), 4.47(s, 2H), 4.91 (s, 2H), 5.07 (s, 2H), 5.85 (s, 1H), 6.84-6.89 (m, 4H),7.12-7.15 (d, 2H, J=9.4 Hz), 7.21-7.23 (d, 2H, J=8.7 Hz), 7.57-7.61 (m,1H), 8.03-8.06 (m, 1H), 8.61-8.63 (d, 1H, J=4.3 Hz), 8.73 (s, 1H).

Example 326-[(2-Amino-4-benzyloxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-1-(4-difluoromethoxy-benzyl)-3-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 270)

To compound 18d (2.8 g, 8.9 mmol) in 100 mL of THF was added DIAD (2.1mL, 10.7 mmol), triphenyl phosphine (17.8 mmol), and compound Xxa. Themixture was allowed to stir at rt under an atmosphere of Argon. Themixture was concentrated, diluted with EtOAc, and washed with water. Theorganic phase was partitioned, dried over MgSO₄, filtered, and thefiltrate was concentrated to a yellow oil. The oil was purified byreverse-phase chromatography to furnish compound XXb.

Compound 270 was prepared by an adaptation of the method described inExample 5, Step F, substituting Compound XXb for Compound 5e, andsubstituting Compound XXc for Compound 2a.

Other compounds of the present invention may be prepared by thoseskilled in the art by varying the starting materials, reagent(s) andconditions used. Using the general procedure of Example 32, thefollowing compounds were prepared:

Cpd MS obs MS calc 261 523.2 522.51 262 631.2 630.63

Example 336-[(2-Amino-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-1-(4-methoxy-benzyl)-3-(5-methoxy-pentyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 252)

Compound 252 was prepared from Compound 8c using an adaptation of themethods described in Example 8, substituting 5-methoxy-pentan-1-ol for2,3-dihydro-1-benzofuran-5-ylmethanol in Step C.

Example 346-[(2-Amino-pyridin-3-ylmethyl)-amino]-1-(4-methoxy-benzyl)-3-(4-[1,2,3]thiadiazol-5-yl-benzyl)-1H-[1,3,5]triazine-2,4-dione(Cpd 240)

A. To Compound 8c (0.028 g, 0.1 mmol) in 0.5 mL CH₃CN was added cesiumcarbonate (0.032 g, 0.1 mmol) followed by the addition of Compound 34a(0.0255 g, 0.1 mmol) and the mixture was stirred at 25° C. for 16 h. Atthat time the mixture was concentrated. The resulting residue waspartitioned between methylene chloride and water, and the organic phasewas dried and concentrated to give Compound 34b.

B. Compound 34b was dissolved in ethanol (0.5 mL) and Compound 1a (0.018mg, 0.15 mmol) was added. The mixture was irradiated at 180° C. for two30 min cycles in a microwave instrument. The reaction was concentrated,the resultant residue was dissolved in DMSO, and the product waspurified and isolated by reverse phase HPLC to afford Compound 240. MSm/z (ES)=529.17 (M+H), 528.59 calc'd.

Using the methods described in the schemes and specific examples, andadaptations thereof, compounds 1 to 272 of Table 1 were prepared.

TABLE 1 Cpd No. A₁ L₁ D W Q  1 3,4-dichloro- CH₂ 4-methoxy- N2-(pyridin-2-yl) phenyl phenylmethyl ethyl-amino  2 3,4-dichloro- CH₂4-methoxy- N pyridin-3-yl phenyl phenylmethyl methyl-amino  3 4-methoxy-CH₂ 4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 4 4-chloro- CH₂ 4-methoxy- N 5-amino- phenyl phenylmethyl pyridin-2-ylmethyl-amino  5 4-chloro- CH₂ 4-methoxy- N 6-amino- phenyl phenylmethylpyridin-3-yl methyl-amino  6 4-methoxy- CH₂ 4-methoxy- N 4-amino- phenylphenylmethyl pyrimidin-5-yl methyl-amino  7 4-methoxy- CH₂ 4-methoxy- CH2-amino- phenyl phenylmethyl pyridin-3-ylmethyl- aminomethyl  84-fluoro- CH₂ 4-methoxy- N 2-amino- phenyl phenylmethylpyridin-3-ylmethyl- amino  9 4-methoxy- CH₂ 4-methoxy- N 2-amino- phenylphenylmethyl quinolin-3- ylmethyl-amino  10 4-fluoro- CH₂ 4-methoxy- N2-(2-amino- phenyl phenylmethyl pyridin-3- yl)-ethylamino  11 4-fluoro-CH₂ 4-methoxy- N 2-N-pyrrolidinyl- phenyl phenylmethylpyridin-3-ylmethyl- amino  12 4-methoxy- CH₂ 4-methoxy- N2-N-piperazinyl- phenyl phenylmethyl pyridin-3-ylmethyl- amino  134-methoxy- CH₂ 4-methoxy- N 2-N-piperidinyl- phenyl phenylmethylpyridin-3-yl methyl-amino  14 4-fluoro- CH₂ 4-methoxy- N 2-methylamino-phenyl phenylmethyl pyridin-3-yl methyl-amino  15 4-fluoro- CH₂4-methoxy- N 2-n-propylamino- phenyl phenylmethyl pyridin-3-ylmethyl-amino  16 4-fluoro- CH₂ 4-methoxy- N 2-n-butylamino- phenylphenylmethyl pyridin-3-ylmethyl- amino  17 4-fluoro- CH₂ 4-methoxy- N2-N-morpholino- phenyl phenylmethyl pyridin-3-yl methyl-amino  184-fluoro- CH₂ 4-methoxy- N 2-N-thiomorpholino- phenyl phenylmethylpyridin-3-yl methyl-amino  19 4-fluoro- CH₂ 4-methoxy- N2-ethylamino-pyridin- phenyl phenylmethyl 3-yl methyl-amino  204-methoxy- CH₂ 4-methoxy- N 2-N-morpholino- phenyl phenylmethylpyridin-3-ylmethyl- amino  21 4-fluoro- CH₂ 4-methoxy- N1,2,3,4-tetrahydro- phenyl phenylmethyl [1,8] naphthyridin-7-ylmethyl-amino  22 4-methoxy- CH₂ 4-methoxy- N 4,6-dimethyl- phenylphenylmethyl pyridin-3- ylmethyl-amino  23 benzofuran- CH₂ 4-methoxy- N2-amino- 2-yl phenylmethyl pyridin-3-yl methyl-amino  24 4-methylthio-CH₂ 4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 25 4-methoxy- CH₂ 4-methoxy- N 6-(4-fluoro-phenyl)- phenyl phenylmethylpyridin-3-yl methyl-amino  26 4-methoxy- CH₂ 4-methoxy- CH 2-aminophenyl phenylmethyl pyridin-3-yl methyl-amino  27 4-fluoro- CH₂4-methoxy- N 2-(2-dimethylamino- phenyl phenylmethylethylamino)-pyridin-3-yl methyl-amino  28 4-fluoro- CH₂ 4-methoxy- N2-(2-methoxy- phenyl phenylmethyl ethylamino)-pyridin-3-yl methyl-amino 29 4-fluoro- CH₂ 4-methoxy- N 2-(2-hydroxy- phenyl phenylmethylethylamino)-pyridin-3-yl methyl-amino  30 4-fluoro- CH₂ 4-methoxy- N2-(2-amino- phenyl phenylmethyl ethylamino)-pyridin-3-yl methyl-amino 31 4-fluoro- CH₂ 4-methoxy- N 2-cyclohexylamino- phenyl phenylmethylpyridin-3-yl methyl-amino  32 4-methoxy- CH₂ 4-methoxy- N N-oxo-2-amino-phenyl phenylmethyl pyridin-3-yl methyl-amino  33 4-methoxy- CH₂4-hydroxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  344-methoxy- CH₂ 4-methoxy- N 2-n-propylamino- phenyl phenylmethylpyridin-3-yl methyl-amino  35 4-methoxy- CH₂ 4- N 2-amino- phenyldifluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino  36 4-methoxy-CH₂ 4- N 2-amino- phenyl methoxycarbonyl- pyridin-3-yl phenylmethylmethyl-amino  37 4-methoxy- CH₂ 4-methylcarbonyl N 2-amino phenyl amino-pyridin-3-yl phenylmethyl methyl-amino  38 4-methoxy- CH₂ 4- N 2-aminophenyl trifluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino  394-methoxy- CH₂ 4-methoxy- N pyridin-2-yl phenyl phenylmethylmethyl-amino  40 4-methoxy- CH₂ 4-methoxy- N pyridin-3-yl phenylphenylmethyl methyl-amino  41 4-methoxy- CH₂ 4-methoxy- N pyridin-4-ylphenyl phenylmethyl methyl-amino  42 3-methoxy- CH₂ 4-methoxy- N2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  43 phenyl CH₂4-methoxy- N 2-amino- phenylmethyl pyridin-3-yl methyl-amino  444-cyano- CH₂ 4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-ylmethyl-amino  45 4-trifluoro CH₂ 4-methoxy- N 2-amino- methoxy-phenylmethyl pyridin-3-yl phenyl methyl-amino  46 4-ethoxy- CH₂4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  474-nitro-phenyl CH₂ 4-methoxy- N 2-amino- phenylmethyl pyridin-3-ylmethyl-amino  48 4-methoxy- CH(allyl) 4-methoxy- N 2-amino- phenylphenylmethyl pyridin-3-yl methyl-amino  49 4- CH₂ 4-methoxy- N 2-amino-trifluoromethyl- phenylmethyl pyridin-3-yl phenyl methyl-amino  504-methoxy- CH₂ 4-methoxy- N 2-(2-methoxy- phenyl phenylmethylethylamino)-pyridin-3-yl methyl-amino  51 4-methoxy- CH₂ 4-methoxy- N2-(2-dimethylamino- phenyl phenylmethyl ethylamino)-pyridin-3-ylmethyl-amino  52 4-methoxy- CH₂ 4-aminocarbonyl- N 2-amino- phenylphenylmethyl pyridin-3-yl methyl-amino  53 4-methoxy- CH₂ 4-methoxy- NN-oxo- phenyl phenylmethyl pyridin-3-yl methyl-amino  54 4-hydroxy- CH₂4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  553-fluoro- CH₂ 4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-ylmethyl-amino  56 4- CH₂ 4-methoxy- N 2-amino- methoxycarbonyl-phenylmethyl pyridin-3-yl phenyl methyl-amino  57 4-methoxy- CH₂4-methoxy- N 2-amino-5-phenyl- phenyl phenylmethyl pyridin-3-ylmethyl-amino  58 4-methoxy- CH₂ 4-methoxy- N 2-amino-4-methoxy- phenylphenylmethyl pyridin-3-yl methyl-amino  59 4-methoxy- CH₂ 4-methoxy- N6-methyl- phenyl phenylmethyl pyridin-3-yl methyl-amino  60 4-fluoro-CH₂ 4-methoxy- N 4,6-dimethyl-pyridin- phenyl phenylmethyl 3-ylmethyl-amino  61 4-methoxy- CH₂ 4-methoxy- CH 4,6-dimethyl-pyridin-phenyl phenylmethyl 3-yl methyl-amino  62 4-methoxy- CH₂ 4-methoxy- N4-methyl- phenyl phenylmethyl pyridin-2-yl methyl-amino  63 4-methoxy-CH₂ 4-ethyl- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 64 4-methoxy- CH₂ 4-methoxy- N 6-trifluoromethyl- phenyl phenylmethylpyridin-2-yl methyl-amino  65 4-methoxy- CH₂ 4-methoxy- N 3-methyl-phenyl phenylmethyl pyridin-2-yl methyl-amino  66 4-methoxy- CH₂4-methoxy- N 2-(2-methylthio- phenyl phenylmethylethylamino)-pyridin-3-yl methyl-amino  67 4-methoxy- CH₂ 4-methoxy- N2-(3-methyl- phenyl phenylmethyl butylamino)-pyridin-3-yl methyl-amino 68 4-methoxy- CH₂ 4-methoxy- N 2-(tetrahydro-furan-2-yl phenylphenylmethyl methyl-amino)-pyridin- 3-yl-methyl-amino  69 4-methoxy- CH₂4-methoxy- N 2-(furan-2-ylmethyl- phenyl phenylmethylamino)-pyridin-3-yl methyl-amino  70 4-methoxy- CH₂ 4-methoxy- N2-(N-ethyl-pyrrolidin-2- phenyl phenylmethylylmethyl-amino)-pyridin-3-yl methyl-amino  71 phenyl CH₂CH₂ 4-methoxy- N2-(2-methoxy- phenylmethyl ethylamino)-pyridin-3-yl methyl-amino  72phenoxy CH₂CH₂ 4-methoxy- N 2-(2-methoxy- phenylmethylethylamino)-pyridin-3-yl methyl-amino  73 2,3-dihydro- CH₂ 4-methoxy- N2-(2-methoxy- benzo[1,4] phenylmethyl ethylamino)-pyridin-3-yldioxin-2-yl methyl-amino  74 4-nitro-phenyl CH₂CH₂ 4-methoxy- N2-(2-methoxy- phenylmethyl ethylamino)-pyridin-3-yl methyl-amino  754-methoxy- CH₂ 4-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-ylmethyl-amino  76 4-methoxy- CH₂ pyridin-4-ylmethyl N 2-amino- phenylpyridin-3-yl methyl-amino  77 4-methoxy- CH₂ benzofuran-2-yl N 2-amino-phenyl methyl pyridin-3-yl methyl-amino  78 4-methoxy- CH₂ 5-methoxy-n-N 2-amino- phenyl pentyl pyridin-3-yl methyl-amino  79 4-methoxy- CH₂n-hexyl N 2-amino- phenyl pyridin-3-yl methyl-amino  80 4-methoxy- CH₂3-methoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  814-methoxy- CH₂ 3-cyano- N 2-amino- phenyl phenylmethyl pyridin-3-ylmethyl-amino  82 4-methoxy- CH₂ 3-nitro- N 2-amino- phenyl phenylmethylpyridin-3-yl methyl-amino  83 4- CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-difluoromethoxy- phenylmethyl 3-yl phenyl methyl-amino  84 4- CH₂4-methoxy- N 2-amino- difluoromethoxy- phenylmethyl pyridin-3-yl phenylmethyl-amino  85 4- CH₂ 4- N 2-amino- difluoromethoxy- difluoromethoxy-pyridin-3-yl phenyl phenylmethyl methyl-amino  86 4-methoxy- CH₂2-ethyl- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino  874-methoxy- CH₂ 2- N 2-amino- phenyl trifluoromethoxy- pyridin-3-ylphenylmethyl methyl-amino  88 4-methoxy- CH₂ 2-cyano- N 2-amino- phenylphenylmethyl pyridin-3-yl methyl-amino  89 4-iodo-phenyl CH₂ 4-methoxy-N 2-amino- phenylmethyl pyridin-3-yl methyl-amino  90 4-pyrazol-1- CH₂4-methoxy- N 2-amino- yl-phenyl phenylmethyl pyridin-3-yl methyl-amino 91 4-fluoro- CH₂ 4- N 2-amino- phenyl trifluoromethoxy pyridin-3-ylphenylmethyl methyl-amino  92 4-methoxy- CH₂ 2-methoxy- N 2-amino-phenyl phenylmethyl pyridin-3-yl methyl-amino  93 4-methoxy- CH₂ 3- N2-amino- phenyl methoxycarbonyl- pyridin-3-yl phenylmethyl methyl-amino 94 4-methoxy- CH₂ 2-(4-methoxy- N 2-amino- phenyl phenyl)-ethylpyridin-3-yl methyl-amino  95 4-methoxy- CH₂ 6-methoxy- N 2-amino-phenyl pyridin-3-ylmethyl pyridin-3-yl methyl-amino  96 4-methoxy- CH₂4- N 4,6-dimethyl-pyridin-3- phenyl difluoromethoxy- ylmethyl-aminophenylmethyl  97 4-methoxy- CH₂ 4-methoxy- N 2-amino-4,6-dimethyl-phenyl phenylmethyl pyridin-3-yl methyl-amino  98 4-methoxy- CH₂ 3- N2-amino- phenyl trifluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino 99 4-methoxy- CH₂ 3- N 4,6-dimethyl-pyridin-3-yl phenyltrifluoromethoxy- methyl-amino phenylmethyl 100 4-methoxy- CH₂4-methylthio- N 4,6-dimethyl-pyridin-3-yl phenyl phenylmethylmethyl-amino 101 4-methoxy- CH₂ pyridin-4-ylmethyl N4,6-dimethyl-pyridin-3-yl phenyl methyl-amino 102 4-methoxy- CH₂benzofuran-2- N 4,6-dimethyl-pyridin-3- phenyl ylmethyl ylmethyl-amino103 4-methoxy- CH₂ n-hexyl N 4,6-dimethyl-pyridin-3-yl phenylmethyl-amino 104 4-methoxy- CH₂ 6-methoxy- N 4,6-dimethyl-pyridin-3-ylphenyl pyridin-3-ylmethyl methyl-amino 105 4-methoxy- CH₂ 2- N4,6-dimethyl-pyridin-3-yl phenyl trifluoromethoxy- methyl-aminophenylmethyl 106 4-methoxy- CH₂ 2-methoxy- N 4,6-dimethyl-pyridin-3-ylphenyl phenylmethyl methyl-amino 107 4-ethoxy- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3-yl phenyl phenylmethyl methyl-amino 1084-nitro-phenyl CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yl phenylmethylmethyl-amino 109 4-methoxy- CH(allyl) 4-methoxy- N4,6-dimethyl-pyridin-3-yl phenyl phenylmethyl methyl-amino 110 4- CH₂4-methoxy- N 4,6-dimethyl-pyridin-3-yl trifluoromethyl- phenylmethylmethyl-amino phenyl 111 3-methoxy- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3-yl phenyl phenylmethyl methyl-amino 112 3-fluoro-CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yl phenyl phenylmethylmethyl-amino 113 pyridin-4- CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-ylylmethyl phenylmethyl methyl-amino 114 4- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3-yl methoxycarbonyl- phenylmethyl methyl-aminophenyl 115 4-methoxy- CH₂ 4-methoxy- N 6-amino- phenyl phenylmethylpyridin-2-yl methyl-amino 116 4-methoxy- CH₂ 4-fluoro- N4,6-dimethyl-pyridin-3-yl phenyl phenylmethyl methyl-amino 1174-methoxy- CH₂ 4-chloro- N 4,6-dimethyl-pyridin-3-yl phenyl phenylmethylmethyl-amino 118 4-methoxy- CH₂ 4-methoxy- N N-oxo-4,6-dimethyl- phenylphenylmethyl pyridin-3-yl methyl-amino 119 indol-3-yl CH₂CH₂ 4-methoxy-N 2-amino- phenylmethyl pyridin-3-yl methyl-amino 120 2,3-dihydro- CH₂4-methoxy- N 2-amino- benzo[1,4] phenylmethyl pyridin-3-yl dioxin-2-ylmethyl-amino 121 4-methoxy- CH₂ 4-methoxy- CH pyridin-3-ylmethoxy phenylphenylmethyl 122 4-methoxy- CH₂ 4-methoxy- N 6-trifluoromethyl- phenylphenylmethyl pyridin-3-ylmethyl- amino 123 2,3-dihydro- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3- benzofuran- phenylmethyl ylmethyl-amino 5-yl 1243-nitro-4- CH₂ 4-methoxy- N 2-amino-pyridin-3- methoxy- phenylmethylylmethyl-amino phenyl 125 4-methoxy- CH₂ 2,3-dihydro- N 2-amino- phenylbenzofuran-5-yl pyridin-3-yl methyl methyl-amino 126 4-methoxy- CH₂benzofuran-5-yl N 2-amino- phenyl methyl pyridin-3-yl methyl-amino 1274-methoxy- CH₂ indol-5-ylmethyl N 2-amino- phenyl pyridin-3-ylmethyl-amino 128 4-methoxy- CH₂ 2,3-dihydro- N 4,6-dimethyl-pyridin-3-ylphenyl benzofuran-5-yl methyl-amino methyl 129 4-methoxy- CH₂benzofuran-5-yl N 4,6-dimethyl-pyridin-3-yl phenyl methyl methyl-amino130 4-methoxy- CH₂ indol-5-ylmethyl N 4,6-dimethyl-pyridin-3-yl phenylmethyl-amino 131 4-methoxy- CH₂ 4- N 2-amino- phenyl methanesulfonyl-pyridin-3-yl phenylmethyl methyl-amino 132 4-methoxy- CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenyl methanesulfonyl- methyl-aminophenylmethyl 133 benzofuran- CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yl5-yl phenylmethyl methyl-amino 134 benzofuran- CH₂ 4-methoxy- N2-amino-pyridin-3- 5-yl phenylmethyl ylmethyl-amino 135 4-methoxy- CH₂4-t-butoxy- N 2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 1364-methoxy- CH₂ 3-nitro-4- N 4,6-dimethyl-pyridin-3-yl phenyl methoxy-methyl-amino phenylmethyl 137 4-methoxy- CH₂ 3-nitro-4- N 2-amino-phenyl methoxy- pyridin-3-yl phenylmethyl methyl-amino 138 4-methoxy-CH₂ indol-4-ylmethyl N 2-amino- phenyl pyridin-3-yl methyl-amino 1394-methoxy- CH₂ indol-4-ylmethyl N 4,6-dimethyl-pyridin-3-yl phenylmethyl-amino 140 4-methoxy- CH₂ benzothiophen-5- N 2-amino- phenylylmethyl pyridin-3-yl methyl-amino 141 4-fluoro- CH₂CH₂ 4-methoxy- N2-amino- phenoxy phenylmethyl pyridin-3-yl methyl-amino 142 4-methoxy-CH₂ benzothiophen-5- N 4,6-dimethyl-pyridin-3-yl phenyl ylmethylmethyl-amino 143 2-methoxy- CH₂ 4-methoxy- N 2-amino- phenylphenylmethyl pyridin-3-yl methyl-amino 144 2-methoxy- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3-yl phenyl phenylmethyl methyl-amino 145benzothiophen- CH₂ 4-methoxy- N 2-amino- 5-yl phenylmethyl pyridin-3-ylmethyl-amino 146 benzothiophen- CH₂ 4-methoxy- N4,6-dimethyl-pyridin-3-yl 5-yl phenylmethyl methyl-amino 147 4-methoxy-CH₂ 4-methoxy- N 6-n-propylamino- phenyl phenylmethyl pyridin-2-ylmethyl-amino 148 4-methoxy- CH₂ 4-methoxy- CH 6-amino- phenylphenylmethyl pyridin-2-yl methyl-amino 149 4-methoxy- CH₂ 4-methoxy- N2-amino- phenyl cyclohexylmethyl pyridin-3-yl methyl-amino 1504-methoxy- CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yl phenylcyclohexylmethyl methyl-amino 151 4-methoxy- CH₂ 3,4-dichloro- N2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 152 4-methoxy-CH₂ 4-(isoindol-1,3- N 4,6-dimethyl-pyridin-3-yl phenyl dione-2-yl)-methyl-amino phenylmethyl 153 4-methoxy- CH₂ 3-methoxy N4,6-dimethyl-pyridin-3-yl phenyl carbonyl-n-propyl methyl-amino 1544-methoxy- CH₂ 4-methoxy- N 2-(pyridin-2-yl)- phenyl phenylmethylethylamino 155 4-methoxy- CH₂ indol-4-ylmethyl N 2-amino-4,6-dimethyl-phenyl pyridin-3-yl methyl-amino 156 4-fluoro- CH₂ 4- N 6-amino- phenyldifluoromethoxy- pyridin-2-yl phenylmethyl methyl-amino 157 4-methoxy-CH₂ 2,3-dihydro- N 2-amino-4,6-dimethyl- phenyl benzofuran-5-ylpyridin-3-yl methyl methyl-amino 158 4-pyrazol-1- CH₂ 4- N4,6-dimethyl-pyridin-3-yl yl-phenyl difluoromethoxy- methyl-aminophenylmethyl 159 4-iodo-phenyl CH₂ 4- N 4,6-dimethyl-pyridin-3-yldifluoromethoxy- methyl-amino phenylmethyl 160 4-fluoro- CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy- methyl-aminophenylmethyl 161 4-methyl- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl phenyldifluoromethoxy- methyl-amino phenylmethyl 162 4- CH₂ 4- N4,6-dimethyl-pyridin-3-yl trifluoromethyl- difluoromethoxy- methyl-aminophenyl phenylmethyl 163 4- CH₂ 4- N 4,6-dimethyl-pyridin-3-yldifluoromethoxy- difluoromethoxy- methyl-amino phenyl phenylmethyl 1644-cyano- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy-methyl-amino phenylmethyl 165 4-methoxycarbonyl- CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy- methyl-aminophenylmethyl 166 phenoxy CH₂CH₂ 4- N 4,6-dimethyl-pyridin-3-yldifluoromethoxy- methyl-amino phenylmethyl 167 4-fluoro- CH₂CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenoxy difluoromethoxy- methyl-aminophenylmethyl 168 4-[1,2,3] CH₂ 4- N 4,6-dimethyl-pyridin-3-ylthiadiazol-4- difluoromethoxy- methyl-amino yl-phenyl phenylmethyl 1694-methoxy- CH₂ 4-methoxy- CH 2-(pyridin-3-yl)-ethyl phenyl phenylmethyl170 4-methoxy- CH₂ indol-6-ylmethyl N 2-amino- phenyl pyridin-3-ylmethyl-amino 171 4-methoxy- CH₂ indol-7-ylmethyl N 2-amino- phenylpyridin-3-yl methyl-amino 172 4-methoxy- CH₂ indol-7-ylmethyl N4,6-dimethyl-pyridin-3-yl phenyl methyl-amino 173 4-methylthio- CH₂ 4- N2-amino-4,6-dimethyl- phenyl difluoromethoxy- pyridin-3-yl phenylmethylmethyl-amino 174 benzothiophen- CH₂ 4- N 2-amino-4,6-dimethyl- 5-yldifluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino 175benzofuran-5- CH₂ 4- N 2-amino-4,6-dimethyl- yl difluoromethoxy-pyridin-3-yl phenylmethyl methyl-amino 176 2,3-dihydro- CH₂ 4- N2-amino-4,6-dimethyl- benzofuran- difluoromethoxy- pyridin-3-yl 5-ylphenylmethyl methyl-amino 177 4-methylthio- CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy- methyl-aminophenylmethyl 178 benzofuran- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl 5-yldifluoromethoxy- methyl-amino phenylmethyl 179 2,3-dihydro- CH₂ 4- N4,6-dimethyl-pyridin-3-yl benzofuran- difluoromethoxy- methyl-amino 5-ylphenylmethyl 180 2-cyano- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl phenyldifluoromethoxy- methyl-amino phenylmethyl 181 4-hydroxy- CH₂ 4- N4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy- methyl-aminophenylmethyl 182 4- CH₂ 4- N 4,6-dimethyl-pyridin-3-ylmethylcarbonyloxy- difluoromethoxy- methyl-amino phenyl phenylmethyl 1834-methoxy- CH₂ 4-methoxy- CH 2-(pyridin-4-yl)-ethyl phenyl phenylmethyl184 4-methoxy- CH₂ 4-methoxy- CH cis-2-pyridin-4-yl-vinyl phenylphenylmethyl 185 2,3-dihydro- CH₂ 2,3-dihydro- N 2-amino-4,6-dimethyl-benzofuran- benzofuran-5- pyridin-3-yl 5-yl ylmethyl methyl-amino 186benzofuran- CH₂ 2,3-dihydro- N 2-amino-4,6-dimethyl- 5-ylbenzofuran-5-yl pyridin-3-yl methyl methyl-amino 187 4-methoxy- CH₂4-methoxy- CH 2-pyridin-2-yl-ethyl phenyl phenylmethyl 188 4-methoxy-CH₂ 4-methoxy- N imidazol[1,2-a]pyridin- phenyl phenylmethyl 8-ylmethyl-amino 189 4-methoxy- CH₂ 4-methoxy- CH 2-(2-aminocarbonyl- phenylphenylmethyl pyridin-3-yl)-ethyl 190 4-methoxy- CH₂ 4-methoxy- CH2-amino- phenyl phenylmethyl pyridin-3-yl methoxy 191 4- CH₂ 4- N4,6-dimethyl-pyridin-3-yl hydroxymethyl- difluoromethoxy- methyl-aminophenyl phenylmethyl 192 1-methyl-1H- CH₂ 4- N 4,6-dimethyl-pyridin-3-ylbenzotriazol- difluoromethoxy- methyl-amino 5-yl phenylmethyl 1932-methoxy- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl phenyl difluoromethoxy-methyl-amino phenylmethyl 194 4- CH₂ 4- N 4,6-dimethyl-pyridin-3-ylaminocarbonyl- difluoromethoxy- methyl-amino phenyl phenylmethyl 1952,6-difluoro-4- CH₂ 4- N 4,6-dimethyl-pyridin-3-yl methoxy-difluoromethoxy- methyl-amino phenyl phenylmethyl 196 benzo[1,2,3] CH₂4- N 4,6-dimethyl-pyridin-3-yl thiadiazol-5-yl difluoromethoxy-methyl-amino phenylmethyl 197 methoxy (CH₂)₅ 4-methoxy- N4,6-dimethyl-pyridin-3-yl phenylmethyl methyl-amino 198 methoxy (CH₂)₅4- N 4,6-dimethyl-pyridin-3-yl difluoromethoxy- methyl-aminophenylmethyl 199 4-methoxy- CH₂ 4-methoxy- CH 2-(2-amino-pyridin-3-phenyl phenylmethyl yl)-ethyl 200 4-methoxy- CH₂ 2,4-dimethoxy- N2-amino- phenyl phenylmethyl pyridin-3-yl methyl-amino 201 4-methoxy-CH₂ 4-methoxy- N 4-methyl- phenyl phenylmethyl pyridin-3-yl methyl-amino202 4-methoxy- CH₂ 4-methoxy- CH 2-amino-4,6-dimethyl- phenylphenylmethyl pyridin-3-ylmethoxy 203 4-methoxy- CH₂ 3-fluoro-4- N2-amino- phenyl methoxy- pyridin-3-yl phenylmethyl methyl-amino 2044-methoxy- CH₂ 3-fluoro-4- N 4,6-dimethyl-pyridin-3-yl phenyl methoxy-methyl-amino phenylmethyl 205 4-methoxy- CH₂ 2-fluoro-4- N 2-amino-phenyl methoxy- pyridin-3-yl phenylmethyl methyl-amino 206 4-methoxy-CH₂ 2-fluoro-4- N 4,6-dimethyl-pyridin-3-yl phenyl methoxy- methyl-aminophenylmethyl 207 benzo(1,3) CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yldioxal-5-yl phenylmethyl methyl-amino 208 benzo(1,3) CH₂ 4- N4,6-dimethyl-pyridin-3-yl dioxal-5-yl difluoromethoxy- methyl-aminophenylmethyl 209 2,3-dihydro- CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-ylbenzo[1,4] phenylmethyl methyl-amino dioxin-6-yl 210 2,3-dihydro- CH₂ 4-N 4,6-dimethyl-pyridin-3-yl benzo[1,4] difluoromethoxy- methyl-aminodioxin-6-yl phenylmethyl 211 4-methoxy- CH₂ 4-methoxy- CHpyridin-3-ylmethylthio phenyl phenylmethyl 212 4-methoxy- CH₂2-methyl-2,3- N 2-amino-4,6-dimethyl- phenyl dihydro- pyridin-3-ylbenzofuran-5-yl methyl-amino methyl 213 4-methoxy- CH₂ 4-methoxy- N2-(N-piperidinyl)-4,6- phenyl phenylmethyl dimethyl-pyridin-3-ylmethyl-amino 214 4-methoxy- CH₂ 4-methoxy- CH 2-(4-amino-pyridin-3-phenyl phenylmethyl yl)-ethyl 215 4-methoxy- CH₂ 4-methoxy- N2-(pyridin-4-yl)- phenyl phenylmethyl ethylamino 216 1-methyl-1H- CH₂4-methoxy- N 4,6-dimethyl-pyridin-3-yl benzo phenylmethyl methyl-aminotriazol-5-yl 217 benzo[1,2,3] CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-ylthiadiazol-5-yl phenylmethyl methyl-amino 218 3-fluoro-4- CH₂ 4-methoxy-N 4,6-dimethyl-pyridin-3-yl methoxy- phenylmethyl methyl-amino phenyl219 benzo(1,3) CH₂ 4- N 2-amino-4,6-dimethyl- dioxal-5-yldifluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino 220 benzo(1,3)CH₂ 4-methoxy- N 2-amino-4,6-dimethyl- dioxal-5-yl phenylmethylpyridin-3-yl methyl-amino 221 1-methyl-1H- CH₂ 4- N2-amino-4,6-dimethyl- benzotriazol- difluoromethoxy- pyridin-3-yl 5-ylphenylmethyl methyl-amino 222 1-methyl-1H- CH₂ 4-methoxy- N2-amino-4,6-dimethyl- benzotriazol- phenylmethyl pyridin-3-yl 5-ylmethyl-amino 223 4-methoxy- CH₂ 4-methoxy- CH 2-(6-amino-pyridin-2-phenyl phenylmethyl yl)ethyl 224 4-methoxy- CH₂ 5-methoxy-n- N2-amino-4,6-dimethyl- phenyl pentyl pyridin-3-yl methyl-amino 2254-methoxy- CH₂ 4-methoxy- CH 1-(2-amino-pyridin-4- phenyl phenylmethylyl)-ethoxy 226 2,3-dihydro- CH₂ 2,3-dihydro- N N-oxo-2-amino-4,6-benzofuran- benzofuran-5-yl dimethyl-pyridin-3-yl 5-yl methylmethyl-amino 227 indol-5-yl CH₂ 4- N 4,6-dimethyl-pyridin-3-yldifluoromethoxy- methyl-amino phenylmethyl 228 indol-5-yl CH₂ 4- N2-amino- difluoromethoxy- pyridin-3-yl phenylmethyl methyl-amino 229indol-5-yl CH₂ 4-methoxy- N 4,6-dimethyl-pyridin-3-yl phenylmethylmethyl-amino 230 indol-5-yl CH₂ 4-methoxy- N 2-amino- phenylmethylpyridin-3-yl methyl-amino 231 4-chloro- CH₂ 4-methoxy- N 2-amino- phenylphenylmethyl pyridin-3-yl methyl-amino 232 4-methoxy- CH₂ 4-methoxy- CH2-amino-pyrimidin-4- phenyl phenylmethyl ylmethoxy 233 2,3-dihydro- CH₂4- N N-oxo-2-amino-4,6- benzofuran- difluoromethoxy-dimethyl-pyridin-3-yl 5-yl phenylmethyl methyl-amino 234 4-methoxy-phenyl CH₂ 4-methoxy phenylmethyl N

235 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

236 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

237 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

238

CH₂ —(CH₂)₅OCH₃ N

239 4-methoxy- phenyl (CH₂)₂ —(CH₂)₅OCH₃ N

240

CH₂ 4-methoxy phenylmethyl N

241 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

242

CH₂

N

243

CH₂

N

244

CH₂

N

245

CH₂

N

246 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

247 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

248 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

249 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl CH

250 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

251

CH₂ 4- difluoromethoxy- phenylmethyl N

252 methoxy (CH₂)₅ 4-methoxy phenylmethyl N

253 4-chloro- phenyl CH₂ —(CH₂)₅OCH₃ N

254 phenyl CH₂ —(CH₂)₅OCH₃ N

255

CH₂ —(CH₂)₅OCH₃ N

256 4-chloro- phenyl CH₂ —(CH₂)₅OCH₃ N

257

CH₂ —(CH₂)₅OCH₃ N

258 4-methoxy- phenyl CH₂ —(CH₂)₅OCH₃ N

259 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

260 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

261

CH₂ 4- difluoromethoxy- phenylmethyl N

262

CH₂ 4- difluoromethoxy- phenylmethyl N

263 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

264 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

265 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

266 CF₃ (CH₂)₂ 4-methoxy phenylmethyl N

267 4-methoxy- phenyl CH₂ 4-methoxy phenylmethyl N

268

CH₂ 4- difluoromethoxy- phenylmethyl N

269

CH₂

N

270

CH₂ 4- difluoromethoxy- phenylmethyl N

271 4-methoxy- phenyl CH₂

N

272 4-methoxy- phenyl CH₂

N

BIOLOGICAL EXAMPLES Biological Example 1 Expression, Isolation, andPurification of Prokineticin-1

Recombinant N-terminal FLAG-tagged human prokineticin-1(sequence-MRGATRVSIMLLLVTVSDCDYKDDDDKAVITGACERDVQCGAGTCCAISLWLRGLRMCTPLGREGEECHPGSHKVPFFRKRKHHTCPCLPNLLCSRFPDGRYRCS MDLKNINF) wasexpressed in stably transfected HEK 293 cells.

HEK 293 cells were grown to 100% confluence in DMEM selectivehigh-glucose media (Invitrogen, Carlsbad, Calif.) containing 10% FBS, 20mM HEPES, sodium pyruvate, penicillin and streptomycin (50 μg/ml each),and G418 (400 mg/L). The DMEM media used to culture the HEK 293 cellswas replenished every other day with fresh media over a two-week periodof time. Culture media containing the PK-1 peptide was collected, andfiltered in 500 mL 0.2 μm pore size filters (Corning Incorporated,Corning, N.Y.). The filtrate was stored in a filtrate bottle at 4 C. ThePK-1 peptide containing media was purified by gravity flow passage ofmedia over M2 agarose columns (Sigma Chemical, St. Louis, Mo.) at 4 C.Following-media passage, the agarose columns were washed with sterile1×PBS (pH 7.4) until protein could no longer be detected by OD 280 nm.Columns were then eluted with a 0.1 M glycine-HCl solution at pH 2.8.The eluted material was immediately neutralized, by collecting intotubes containing 1M Tris pH8. Peak fractions were identified by OD 280and pooled. The pooled fractions were subjected to Enterokinase cleavageof Flag epitope 4 units/mL overnight at room temperature. Enterokinasewas removed, and sample aliquot was stored at −80 C.

Results of Mass Spectral Analysis of Prokineticin 1 Ligand from AbovePurification

The samples were analyzed using Maldi TOF-MS and LC-Electrospray-MassSpectral Analysis.

Desired Protein Sequence:

AVITGACERDVQCGAGTCCAISLWLRGLRMCTPLGREGEECHPGSHKVPFFRKRKHHTCPCLPNLLCSRFPDGRYRCSMDLKNINFCalculated Avg. Molecular Mass=9667.4.MALDI-TOF AnalysisSample Preparation

The protein sample solution (10 μL) was desalted using a C4 Zip Tipaccording to the User Guide for Reversed-Phase ZipTip, 2002 MilliporeCorporation.

Mass Spectrometry

A Micromass TOF Spec E mass spectrometer was used to determine molecularmass. MassLynx software 3.4 was used for the system control and dataacquisition. MALDI positive ion mass spectra were acquired over a massrange of 0-80,000 Da. The raw MS data were baseline subtracted andsmoothed using Masslynx software and compared to the masses obtainedfrom a reference standard.

Masses of eluting components were calculated using the Agilentdeconvolution software.

Results

The mass spectral data shows the presence of the desired protein(molecular mass=9667) and an additional related component with ameasured molecular mass of 9172 in about the same abundance based onmass spectral response. This mass agrees, within measurement error, witha possible truncation product missing the last four C-terminal residuesindicated below.

Proposed Additional Protein Component Sequence

AVITGACERDVQCGAGTCCAISLWLRGLRMCTPLGREGEECHPGSHKVPFFRKRKHHTCPCLPNLLCSRFPDGRYRCSMDLK.Calculated Avg. Molecular Mass=9178.8. No other related protenaceouscomponents were detected. The mass accuracy for all measurements isapproximately 0.1%.

Biological Example 2 Functional Assay Screening Procedure for PK1Antagonists on the Fluorometric Imaging Plate Reader (FLIPR)

At a time of 24 h prior to running the assay, in cell culture media(DMEM containing high Glucose and L-glutamine, 10% FBS, 1%Pen/Streptomycin, 1% Sodium Pyruvate, 20 mM HEPES, Zeocin 200 mg/L), 100μL of 1.3*10⁶/ml HEK 293 GPR73 (prokineticin 1 receptor) expressingcells were plated in a 96 well poly-d-lysine coated plate (Costar), andincubated at 37 C and 5% CO₂. On the day in which the assay was run, themedia was removed and 200 μL of 5× Calcium Plus Dye (Molecular Devices)which was previously resuspended with 200 mL of assay buffer [HBSS w/Ca²⁺ and Mg²⁺ w/o phenol red, 20 mM HEPES, 0.1% BSA, 10 mL probenecid(710 mg probenecid in 5 mL of 1N NaOH, to which was then added 5 mL HBSScontaining 20 mM HEPES)] was added to each well of the 96-well plate.The plate was incubated at 37 C and 5% CO₂ for 30 min in dark. The platewas removed and allowed to reach RT for 15 min in the dark. The assaywas then run on the FLIPR. In Brief: base line read for 1 min, compoundadded (25 μL) and incubated for 4 min, 15 seconds, PK1 ligandpreparation added (25 μL) for a final concentration of a previouslydetermined EC₅₀ and fluorescence was counted for 1 min, 45 seconds.Baseline is described as the amount of relative fluorescence read whenbuffer alone is added to cells. Baseline was subtracted from all wells.Percent of control was calculated as follows:

(Baseline subtracted well value is divided by baseline subtracted maxvalue)*100. Percent inhibition is 100 minus the percent of controlvalue.

The IC₅₀ is defined as the amount of a given compound required toinhibit 50% of the maximum signal that is generated by the concentrationof PK1 preparation used in our assay. IC₅₀ values were calculated usingGraphPad Prism.

Table 2 includes data generated from the PK1 functional assay describedin Example 2.

TABLE 2 Ca²⁺ Mobilization Ca²⁺ Mobilization % Inh Cpd IC₅₀ (μM) @ 10 μM1 >10 37 2 >10 47 3 0.034, 0.061. 83, 94, 100* 0.082* 4 0.357 94 5 1.1281 6 0.176 90 7 6.2 60 8 0.535, 0.669 89, 86 9 0.295 95 10 1.25 82 116.79 54 12 1.29 74 13 0.544 72 14 0.793 90 15 0.327 95 16 0.348 89 172.43 73 18 5.48 58 19 0.885 83 20 0.177 95 21 0.656 85 22 0.009, 0.070,88, 96, 97* 0.105* 23 0.231 97 24 0.115 60 25 2.74 89 26 0.045 84 270.088 102 28 0.046, 0.339, 85, 90, 91* 0.847* 29 0.11 111 30 1.24 68 310.939 91 32 1.22 78 33 0.049, 0.077 95, 102 34 0.081 98 35 0.034 85 360.27 84 37 0.25 86 38 0.391 91 39 0.063, 0.082 92, 95 40 0.557 83 411.06 72 42 >10 49 43 0.801 78 44 2.02 66 45 >10 40 46 0.522 80 47 0.82680 48 0.956 75 49 3.17 64 50 0.024, 0.072 91, 100 51 0.207 93 52 0.97394 53 >10 45 54 3.47, >10 42, 64 55 >10 44 56 >10 47 57 4.77 59 58 0.08995 59 0.178 94 60 0.35 88 61 0.036, 0.697 87, 101 62 2.03 52 63 0.271 8364 5.26, 8.51 50, 51 65 >10 8, 32 66 0.401 92 67 4.82 55 68 0.217 95 690.337 93 70 0.560 94 71 >10 38 72 1.17 81 73 5.93 58 74 7.46 54 75 0.13199 76 1.46 67 77 0.449 91 78 0.036, 0.113 94, 95 79 0.679 85 80 2.03 7081 >10 36 82 >10 38 83 0.668 82 84 1.22 70 85 4.5 62 86 >10 31 87 >10 5388 >10 41 89 0.817 82 90 2.33 71 91 3.98 59 92 5.16 58 93 0.116 96 940.373 91 95 0.084 92 96 0.273 92 97 0.006, 0.007, 90, 96, 98* 0.019* 980.736 77 99 0.1 91 100 0.533 62 101 3.3 60 102 0.11 99 103 >10 41 1040.193 96 105 0.437 85 106 0.025, 0.074 99, 101 107 0.868 89 108 >10 42109 0.681 89 110 9.07 48 111 7.88 57 112 2.55 74 113 >10 42 114 6.31 48115 0.244 98 116 0.391 95 117 0.218 97 118 1.37 80 119 >10 40 120 >10 40121 6.33 58 122 0.194 76 123 0.684 83 124 0.815 61 125 0.054, 0.014 97,99 126 0.232 89 127 0.607 81 128 0.126, 0.214 93, 98 129 0.120 88 1300.245 92 131 0.122 100 132 0.247 79 133 0.582 88 134 0.225 86 135 0.18694 136 0.015, 0.034 92, 102 137 1.04 68 138 1.512, 2.7 61, 73 139 0.011,0.021, 92, 97, 100* 0.260* 140 0.192 91 141 1.13 82 142 0.387 76 143 >1031 144 >10 36 145 0.317 90 146 2.14 80 147 0.110 99 148 0.503 86 1490.788 86 150 0.595 78 151 2.40 60 152 0.240 91 153 0.703 81 154 0.657,0.952 79, 80 155 0.002, 0.007 98, 100 156 3.22 70 157 0.004, 0.011 92,96 158 3.84 62 159 >10 31 160 0.628 71 161 4.78 53 162 >10 31 163 >10 38164 2.01 64 165 6.15 52 166 1.70 73 167 2.62 65 168 1.52 68 169 0.226,0.973 78, 86 170 0.032 96 171 >10 46 172 0.515 88 173 0.207 97 174 0.29087 175 0.057, 0.093 96, 99 176 0.023, 0.048, 96, 98 0.130* 177 0.640 79178 8.65 46 179 4.53 61 180 >10 37 181 3.73 61 182 8.51 55 183 2.46 68184 2.69 65 185 0.015, 0.080, 0.118* 92, 94, 98* 186 0.074, 0.097 99,100 187 >10 41 188 0.579 66 189 >10 38 190 0.502 79 191 8.37 50 1920.146, 1.06 80, 82 193 >10 39 194 6.22 49 195 0.374, >10 23, 89 1960.451 84 197 2.84 54 198 1.04 64 199 0.169, 0.691 92, 95 200 0.304 87201 0.327 95 202 0.830 70 203 0.060 103 204 0.068 102 205 0.106 102 2060.046 102 207 0.461, 0.471 92, 93 208 1.27 73 209 7.73 51 210 >10 39 2114.58 52 212 0.021, 0.050 103, 99 213 >10 45 214 7.16 53 215 0.5, 2.78104, 68 216 1.065 80 217 1.01 81 218 0.104 94 219 0.136, 0.158 94, 97220 0.043 98 221 0.045, 0.072 98, 96 222 0.06 98 223 5.68 53 224 0.007,0.011 97 225 3.78 68 226 0.922 85 227 >10 44 228 3.40 63 229 >10 41 2302.75 66 231 0.245 89 232 >10 33 233 0.069, 0.130 96, 97 234 2.59 66 2350.085 98 236 1.27 64 237 1.68 69 242 0.251 95 243 0.914 75 244 0.121 94245 >10 45 246 8.32 48 247 0.027, 0.030 100, 97 248 0.034 103 249 0.19490 250 8.63 48 251 0.225 93 252 1.35 71 253 0.009 97 254 0.098 96 2550.078 99 256 0.118 99 257 1.52 76 261 0.772 87 262 >10 0.89 263 0.094 99264 0.074 95 265 0.441 95 266 >10 36 267 >10 10 268 >10 24 269 >10 22270 >10 12 271 0.357 89 272 >10 45 Where multiple values are displayedfor a single compound. These values representative of values determinedupon multiple testing.

Biological Example 3 Effect of PK1 on Secretion and Gut Mucosal IonTransport in Mammals

Methodology. Segments of ileum starting at a point 2 cm proximal to theileocecal junction and extending 10 cm proximally were freshly excised,placed into Krebs-Ringer bicarbonate (KRB) solution, and emptied oftheir contents as a plastic rod was gently inserted into the intactsegment. Ileal segments were scored with the back-edge of scalpel bladealong the entire mesenteric border, and the intact muscular layersincluding the myenteric plexus were carefully removed with flat-headforceps. Three rectangular tissue sheets approximately 1.5 cm in lengthwere prepared from the remaining muscle-stripped, mucosa-submucosatissues and cut with care taken to avoid Peyer's patches. Each tissuesheet containing intact submucosal ganglia was pinned over a rectangularportal (total cross-sectional area of exposed mucosa=0.50 cm²) betweenhalves of an acrylic mounting cassette that was inserted between thetissue-bathing reservoirs of a modified Ussing-type flux chamber(Physiologic Instruments, Inc., San Diego, Calif.).

The apical (i.e., mucosal) and basolateral (i.e., serosal) surface ofeach tissue was bathed with 6 ml of an oxygenated KRB solutionmaintained at 36 C. Once mounted, tissues were allowed to equilibratefor 0.5-1 h before electrical field stimulation and addition ofsecretagogues or drugs. The KRB solution contained (in mM) 120 NaCl, 6KCl, 1.2 MgCl₂, 1.2 NaH₂PO₄, 14.4 NaHCO₃, 2.5 CaCl₂, and 11.5 glucose or11.5 mannitol. The KRB solution was continuously aerated with 95% O₂: 5%CO₂ and maintained at pH 7.3. Each chamber was equipped with a pair ofsaturated KCl-agar bridges for measurement of transmural electricalpotential difference (PD) across the tissue, and a pair of Ag—AgCl agarelectrodes connected to an automated voltage-clamp device (model VCCMC6, or model VCC MC8, Physiologic Instruments, Inc., San Diego, Calif.)that compensated for solution resistance between the PD-sensing bridgesand for deviations detected from a transmural potential difference (PD)across the tissues that were clamped at 0 mV. Tissue conductance (G) wascalculated (in mS) by determining the current necessary to change PD by1 mV using bipolar pulses from a pulse generator. Short-circuit current(Isc in μA), an index of net active ion transport, was measuredcontinuously. Tissue conductance (Gt in mS), an index of the barrierfunction to passive flow of ions, was calculated from changes in Isc andthe transepithelial potential difference for each tissue.

Baseline recordings of short-circuit current (Isc) and G for each tissuewere acquired and recorded for an additional 15 min period prior to thestart of an experimental protocol. Stimulated changes in Isc weremeasured and recorded continuously with a computerized data acquisitionsystem (PowerLab 8SP, ADInstruments, Inc., Colorado Springs, Colo.).Neurally-evoked changes in Isc were obtained by application ofelectrical field stimulation (80V, 0.5 ms, 10 Hz, 5 s) from the outputsof an electronic stimulator (S-48, Grass-Telefactor, Astro-Med, Inc.,West Warwick, R.I.) attached via aluminum foil electrodes placed indirect contact with the mucosal surface at opposite poles of eachtissue. Pharmacological agents and secretagogues were routinely added tothe basolateral-side reservoir. Agonist or secretagogue effects on Iscwere continuously recorded following basolateral addition.Concentration-response curves were constructed from the cumulative,step-wise addition of pre-determined increasing amounts of agonist orsecretagogue that were added at or near the peak Isc response to thepreceding lower concentration. Effects of antagonists or inhibitors ofsecretion were evaluated after a 10-20 minute exposure period that wasfollowed by challenge with a specific agonist or secretagogue.

Statistical Analysis. All values are reported as means±SE.Electrophysiological data obtained with Ussing flux-type chambers werenormalized to tissue surface area and expressed per cm². Stimulatedchanges in ion transport were determined as the absolute differencebetween a baseline value prior to stimulation and the maximal response(ΔIsc) evoked by a given stimulus or secretagogue. An estimated EC₅₀ forthe stimulatory action of PK1 on epithelial secretion was determinedfrom a 7-point cumulative concentration-response test using a computercalculated curve-fitting function in PRISM (GraphPad Software, Inc.). Anunpaired, two-tailed Students t-test was used to determine statisticalsignificance between any two groups, e.g., control and experimentaltissues. An ANOVA in conjunction with a post hoc Neuman-Keuls multiplecomparisons test was used to determine significant differences amongmultiple groups. P<0.05 was considered statistically significant.

Summary of results. The basal Isc was 35.2±2.4 μA/cm² and tissueconductance (G) was 33.7±0.9 mS/cm² (n=79 tissues from 34 rats).Following a single-dose addition of PK1 to the Krebs solution bathingthe basolateral tissue surface, Isc gradually increased to a peak valuewithin 2-4 min and then declined back toward baseline within 10-15 min.The PK1-evoked increases in Isc were concentration dependent with anEC₅₀ of approximately 8.2 nM determined from cumulativeconcentration-response studies (see FIG. 2). The maximal response forthe PK1-evoked response occurred at 100 nM; 100 nM PK1 evoked anincrease in Isc of 28.7±2.9 μA/cm² from baseline (n=42 tissues from 29rats) and 10 nM PK1 evoked an increase of 13.5±2. μA/cm² (n=33 tissuesfrom 22 rats). The concentrations of 10 nM and 100 nM were used in allsubsequent studies. PK1 had no significant effect on G in any of ourstudies. The pro-secretory effect of PK1 was not blocked in the presenceof the nerve conduction toxin, Tetrodotoxin (TTX), or blockade ofmuscarinic receptors present on mucosal enterocytes by theanti-cholinergic drug, Atropine, indicating that the its action is notdependent on intrinsic neural activity in the tissues. The PK1 evokedincrease in Isc requires the presence of endogenous PK1 receptors sinceexogenous PK1 peptide added to ileum mucosal tissues from PK1 receptorknock-out mice failed to elicit a significant change in Isc compared towild-type littermates.

Biological Example 4 Small Molecule PK1 Receptor Antagonists areEffective at Suppressing Both PK1 and Cholera Toxin Stimulated GutSecretion in Rat Ileum

Methodology. The basic methodology for Ussing-type ion flux chambersused in these studies was the same as that described in detail abovewith the following modifications to the experimental protocol. Followinga 30-45 minute equilibration period, baseline-stable tissues weresubjected to a train of electrical field stimulation (EFS; 80 V, 0.5 ms,10 Hz, 5 s) applied from contacts connecting the foil electrodes onopposite poles of the tissue to the polarized, isolated outputs from anelectronic square-pulse stimulator. The responses to two sequential EFSwere used to gauge tissue viability and comparability of the responsesof individual tissues from each rat and between rats. Tissue conductancewas measured at periodic intervals as changes in the amplitudes of briefshort-circuit current responses evoked by application of 1 mV amplitudebi-polar pulses from a pulse generator using Ohm's Law. Three to fourtissues from each rat were studied. The tissues from a given animal weregrouped and assigned accordingly: one control tissue which received onlyvehicle followed by two consecutive doses of PK-1 ligand added in acumulative fashion to the basolateral surface of the tissue; theremaining two to three tissues from the same animal were assigned to beexposed to a given PK-1 receptor antagonist (e.g., 3-4 tissues from 1rat: Control, Antagonist₁, Antagonist₂, and/or Antagonist₃). Testcompound was added to the basolateral tissue side reservoir at a finalconcentration of 1 μM and allowed a 15 minute incubation period prior tochallenge with the PK1 peptide. At the end of this 15 min exposureperiod, PK1 ligand at 10 and 100 nM was added in a cumulative fashion toeach tissue to characterize the inhibitory effect of the test compound.At the conclusion of the experiment, EFS was re-applied to gauge tissueviability and stability of responsiveness.

For the Cholera toxin studies, paired mucosal tissues were obtained fromeach rat and mounted in Ussing-type chambers. Following tissueequilibration, baseline-stable and conductance-stable tissues wereexposed to 1 μg/ml Cholera toxin (i.e., one tissue from each pair) addedto the mucosa together with simultaneous addition of DMSO vehicle orCompound 3 of the present invention (i.e., one tissue from each pair) tothe serosa at a final concentration of 10 μM to start the experiment.From this point on, baseline Isc and periodic assessment of tissueconductance were monitored and recorded for up to 4 hours.

Summary of results. Pre-treatment of tissues with PK1 antagonists alonehad no measurable effect on baseline Isc and tissue conductance (G). Theresults indicate that suppression of the PK1 evoked increase in Isc inisolated rat ileum mucosa was successfully achieved in the presence ofCompound 3 of the present invention, which was identified using afunctional cell based screening assay (i.e., mobilization ofintracellular Ca²⁺) as a putative antagonist at the PK1 receptor. Intrials with this compound, the observed suppression of the Isc responseevoked by two ascending cumulative concentrations of PK1 showedcharacteristics of a significant surmountable antagonism (see FIG. 3).These data strongly suggest that good efficacy can be achieved in theselective functional blockade of the PK1 receptor by this small moleculeinhibitor to modulate the pro-secretory effect of PK1 on the intestinalepithelium. The selectivity of the functional blockade of the PK1receptor by Compound 3 was confirmed by testing this compound against anunrelated cholinergic secretagogue, carbachol. Compound 3 failed tosuppress the pro-secretory effect of carbachol tested at two differentconcentrations added in an ascending cumulative fashion to the serosalside of each tissue in the Ussing-type flux chambers (see FIG. 4).

To investigate the potential anti-secretory efficacy of selective smallmolecule PK1 receptor antagonists, we established a model of secretorydiarrhea ex vivo in the Ussing-type flux chambers with mucosal exposureto Cholera toxin. Mucosal application of Cholera toxin mimics the routeof exposure for this disease-causing agent in animals and man.Pre-treatment of isolated rat ileum mucosa with Compound 3 (10 μM addedto the serosa), did significantly suppress the sustained increase inbaseline Isc over time evoked by 1 μg/ml Cholera toxin added to themucosa by approximately 50-60% (see FIG. 5). These data suggest thepotential for the efficacious use of PK1 receptor antagonists from thischemical class in gut disease states that have a significant secretorydiarrhea component.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I):

wherein: A₁ is CF₃, C₁₋₄alkoxy, aryl, aryloxy, benzofused heterocyclyl,or heteroaryl; wherein aryl, aryloxy, and heteroaryl are optionallysubstituted with pyrazol-1-yl or [1,2,3]thiadiazol-4-yl; or aryl,aryloxy, the benzo portion of benzofused heterocyclyl, and heteroarylare optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl,C₁₋₆alkoxy, halogen, nitro, halogenated C₁₋₆alkyl, halogenatedC₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, cyano, hydroxy, aminocarbonyl,C₁₋₆alkylaminocarbonyl, di(C₁₋₆alkyl)aminocarbonyl,C₁₋₆alkoxycarbonylamino, C₁₋₆alkylcarbonyl, C₁₋₆alkylthiocarbonyl,formyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonylamino, aminosulfonyl,C₁₋₆alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl; provided that A₁is other than 3,5-di-t-butyl-phenyl; L₁ is —(CH₂)_(r)—,—CH₂C₂₋₄alkenyl-, or —CH₂CH₂X(CH₂)_(s)—, wherein L₁ is optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and halogen;and, r is an integer of 1 to 5; such that r is greater than or equal to4 when A₁ is C₁₋₄alkoxy; s is an integer of 1 to 3; X is O or S; D is—P-A₂; wherein P is —(CH₂)₁₋₂— or —CH₂CH═CH— when A₂ is phenyl,benzofused heterocyclyl, heteroaryl, or C₃₋₈cycloalkyl; alternatively, Pis —(CH₂)₃₋₆— when A₂ is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl;and wherein P is optionally substituted with one to two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, and halogen; A₂ is hydrogen, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, phenyl, benzofused heterocyclyl, heteroaryl,tetrahydro-pyranyl, piperidinyl, or C₃₋₈cycloalkyl; wherein phenyl,heteroaryl, the benzo portion of benzofused heterocyclyl, andC₃₋₈cycloalkyl are optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, halogenated C₁₋₆alkyl, halogenated C₁₋₆alkoxy,aryl(C₁₋₆)alkoxy, phenyl, N-isoindole-1,3-dione, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, cyano, hydroxy, nitro, C₁₋₆alkylcarbonyl,C₁₋₆alkylthiocarbonyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl,di(C₁₋₆alkyl)aminocarbonyl, C₁₋₆alkylcarbonylamino, and a non fusedC₃₋₆cycloalkyloxy; such that no more than two substituents on A₂ arearyl(C₁₋₆)alkoxy, phenyl, N-isoindole-1,3-dione, or a non fusedC₃₋₆cycloalkyloxy; provided that A₂ is other than 3,5-di-t-butyl-phenyl;W is N; Q is selected from the group consisting of (a) to (e), wherein(a) is —NH(CH₂)₂—Ar₁ wherein Ar₁ is pyridinyl optionally substituted oneto three C₁₋₄alkyl substituents or a substituent selected from the groupconsisting of C₁₋₄alkoxy and amino; provided that when Ar₁ isunsubstituted pyridin-3-yl or unsubstituted pyridin-4-yl, and A₂ is4-methoxy-phenyl, A₁ is other than unsubstituted phenyl or3,4-dichloro-phenyl; (b) is —NHCH(R_(z))—Ar₂ wherein R_(z) is H orC₁₋₃alkyl; Ar₂ is pyridinyl, pyrimidinyl, pyrazinyl,

 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position; andwherein Ar₂ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,trifluoromethyl, hydroxyl-C₁₋₄alkyl, amino(C₁₋₄)alkyl,(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl,C₁₋₄alkoxy, C₃₋₈ cycloalkylamino, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; or Ar₂ is optionally substituted with one aminogroup and three substituents independently selected from the groupconsisting of C₁₋₄alkyl and C₁₋₄alkoxy; wherein the C₁₋₆alkyl group of(C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionally substituted withamino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino,C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, a 5 to 6 membered heteroaryl, or a 5to 6 membered heterocyclyl; wherein a nitrogen atom of the 5 to 6membered heterocyclyl is optionally substituted with a C₁₋₄alkylsubstituent; and wherein pyridin-2-yl and pyridin-3-yl are optionallyfurther substituted with N-pyrrolidinyl, N-piperazinyl, N-piperidinyl,N-morpholinyl, N-thiomorpholinyl, —CH₂—O—CH₂—PH, and phenyl; wherein thephenyl substituent of pyridin-2-yl and pyridin-3-yl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, and halogen; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is pyridin-4-yl,4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or 4-methanesulfonyl-phenyl, A₂is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or —(CH₂)₅—, and A₁ ismethoxy, A₂ is other than 4-difluoromethoxy-phenyl or 4-methoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ isbenzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—, and A₁ ispyrrol-1-yl, A₂ is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is 4-nitro-phenylor ethoxy, A₂ is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl,3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; (c) is—CH₂NHCH₂—Ar₃, wherein Ar₃ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthat the point of attachment to quinolinyl is at the 2, 3, or4-position; wherein Ar₃ is optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₄alkyl, amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; and wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)aminoand di(C₁₋₆alkyl)amino is optionally substituted with amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy,or hydroxy; (d) is —(CH₂)₂—Ar₄, wherein Ar₄ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;wherein Ar₄ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy; (e) is —CH═CH—Ar₅; whereinAr₅ is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl,imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point ofattachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7position, and the point of attachment to quinolinyl is at the 2, 3, or4-position; wherein Ar₅ is optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₄alkyl, amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy; wherein R₁ is hydrogen orC₁₋₄alkyl, and Ar₆ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position;wherein Ar₆ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy; and provided that when Q is—O—CH(R₁)-Ar₆, A₁ and A₂ are 4-methoxy-phenyl, and R₁ is hydrogen, Ar₆is other than unsubstituted pyridin-2-yl or 2-amino-pyridin-4-yl;wherein Ar₇ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,amino(C₁₋₄)alkyl, (C₁₋₄alkyl)amino-(C₁₋₄)alkyl,di(C₁₋₄alkyl)amino-(C₁₋₄)alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy; provided that when Q is—O(CH₂)₂—Ar₇ and A₁ and A₂ are 4-methoxy-phenyl, Ar₇ is other thanunsubstituted pyridin-2-yl or unsubstituted pyridin-3-yl; wherein anitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, and Ar₇ is optionallysubstituted with oxo; or an enantiomer, a diastereomer, a tautomer, anda pharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein A₁ is aryl, heteroaryl, or a benzofused heterocyclyl selectedfrom the group consisting of benzo[1,3]dioxalyl and2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, nitro, fluoro, chloro,iodo, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, and C₁₋₄alkylthio;provided that A₁ is other than 3,5-di-t-butyl-phenyl.
 3. The compound ofclaim 1 wherein A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,benzo[1,3]dioxalyl, or 2,3-dihydro-benzofuranyl; wherein phenyl issubstituted with, and benzotriazolyl and benzofuranyl are optionallysubstituted with, one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, nitro, fluoro, chloro,iodo, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, and C₁₋₄alkylthio;provided that A₁ is other than 3,5-di-t-butyl-phenyl.
 4. The compound ofclaim 2 wherein A₁ is aryl, heteroaryl, or a benzofused heterocyclylselected from the group consisting of benzo[1,3]dioxalyl and2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₃alkyl, methoxy, fluoro, chloro,trifluoromethyl, trifluoromethoxy, and methylthio.
 5. The compound ofclaim 4 wherein A₁ is substituted phenyl, heteroaryl, or a benzofusedheterocyclyl selected from the group consisting of benzo[1,3]dioxalyland 2,3-dihydro-benzofuranyl; wherein substituted phenyl and heteroarylare optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₃alkyl, methoxy, fluoro andmethylthio.
 6. The compound of claim 5 wherein A₁ is substituted phenyl,benzotriazolyl, benzofuranyl, benzo[1,3]dioxalyl, or2,3-dihydro-benzofuranyl; wherein phenyl is substituted at the4-position with methoxy, fluoro, or methylthio; and wherein A₁ otherthan substituted phenyl is optionally substituted with one to twosubstituents independently selected from the group consisting of methyl,methoxy, fluoro and methylthio.
 7. The compound of claim 1 wherein L₁ is—(CH₂)_(r)—, wherein L₁ is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₄alkyl and C₂₋₄alkenyl and r is 1 or
 2. 8. The compound of claim 7wherein L₁ is —CH₂—.
 9. The compound of claim 1 wherein P is —(CH₂)₁₋₂—when A₂ is phenyl, benzofused heterocyclyl, heteroaryl, orC₃₋₈cycloalkyl; alternatively, P is —(CH₂)₄₋₆— when A₂ is hydrogen,C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl.
 10. The compound of claim 9 wherein Pis —CH₂— when A₂ is phenyl, benzofused heterocyclyl, heteroaryl, orC₃₋₈cycloalkyl; alternatively, P is —(CH₂)₄₋₆— when A₂ is hydrogen,C₁₋₄alkoxy, or C₁₋₄alkoxycarbonyl.
 11. The compound of claim 1 whereinA₂ is hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl, benzofusedheterocyclyl, heteroaryl other than pyridin-4-yl, or C₃₋₈cycloalkyl;wherein phenyl, heteroaryl, and C₃₋₈cycloalkyl are optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, fluoro, chloro, halogenatedC₁₋₆alkoxy, phenyl, N-isoindole-1,3-dione, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl, nitro, hydroxy, andC₁₋₆alkylcarbonylamino; provided that no more than one substituent of A₂is phenyl or N-isoindole-1,3-dione; and provided that A₂ is other than3,5-di-t-butyl-phenyl.
 12. The compound of claim 11 wherein A₂ isC₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl other thanpyridin-4-yl; wherein phenyl and heteroaryl are optionally substitutedwith one to two substituents independently selected from the groupconsisting of C₁₋₄alkyl, C₁₋₄alkoxy, fluoro, chloro, halogenatedC₁₋₄alkoxy, N-isoindole-1,3-dione, C₁₋₄alkylthio, C₁₋₄alkylsulfonyl,C₁₋₄alkoxycarbonyl, nitro, hydroxy, and C₁₋₄alkylcarbonylamino; providedthat no more than one substituent of A₂ is N-isoindole-1,3-dione; andprovided that A₂ is other than 3,5-di-t-butyl-phenyl.
 13. The compoundof claim 12 wherein A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl,or a heteroaryl other than pyridin-4-yl; wherein phenyl and heteroarylare optionally substituted with one to two substituents independentlyselected from the group consisting of C₁₋₄alkoxy, fluoro, halogenatedC₁₋₄alkoxy, C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro,and hydroxy.
 14. The compound of claim 13 wherein A₂ is C₁₋₄alkoxy,phenyl, 2,3-dihydro-benzofuranyl, indolyl, benzofuranyl, pyridin-3-yl,or benzothiophenyl; wherein A₂ other than C₁₋₄alkoxy is optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₄alkoxy, fluoro, fluorinated C₁₋₄alkoxy,C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, andhydroxy.
 15. The compound of claim 1 wherein Q is selected from thegroup consisting of (a)-(e) wherein: (a) is —NH(CH₂)₂—Ar₁ wherein Ar₁ ispyridinyl substituted with one to three C₁₋₄alkyl substituents or asubstituent selected from the group consisting of C₁₋₄alkoxy and amino;(b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position; andwherein Ar₂ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,trifluoromethyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, a 5 to 6membered heteroaryl, or a 5 to 6 membered heterocyclyl; wherein anitrogen atom of the 5 to 6 membered heterocyclyl is optionallysubstituted with a C₁₋₄alkyl substituent; and wherein pyridin-2-yl andpyridin-3-yl are optionally further substituted with N-pyrrolidinyl,N-piperazinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, andphenyl; wherein the phenyl substituent of pyridin-2-yl and pyridin-3-ylis optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, andhalogen; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ ispyridin-4-yl, 4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or —(CH₂)₅—,and A₁ is methoxy, A₂ is other than 4-difluoromethoxy-phenyl or4-methoxy-phenyl; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl),and A₁ is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—,and A₁ is pyrrol-1-yl, A₂ is other than 4-methoxy-phenyl; provided thatwhen Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is4-nitro-phenyl or ethoxy, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl,A₂ is other than 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl,3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; (c) is—CH₂NHCH₂—Ar₃, wherein W is N or CH, and Ar₃ is pyridinyl optionallysubstituted with amino; (d) is —(CH₂)₂—Ar₄, wherein Ar₄ is pyridinyl, orpyrimidinyl; wherein Ar₄ is optionally substituted with one to twosubstituents independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, and di(C₁₋₆alkyl)amino;(e) is —CH═CH-pyridinyl; and wherein R₁ is hydrogen or C₁₋₄alkyl, andAr₆ is pyridinyl or pyrimidinyl; wherein Ar₆ is optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; and wherein theC₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)amino is optionallysubstituted with amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy; provided that when Q is—O—CH(R₁)—Ar₆, A₁ and A₂ are 4-methoxy-phenyl, and R₁ is hydrogen, Ar₆is other than unsubstituted pyridin-2-yl or 2-amino-pyridin-4-yl;wherein a nitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄, Ar₆, and Ar₇ isoptionally substituted with oxo.
 16. The compound of claim 15 wherein Qis selected from the group consisting of (b) and (d) wherein: (b) is—NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl, or quinolinyl; suchthat the point of attachment to quinolinyl is at the 2, 3, or4-position; and wherein Ar₂ is optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy, amino, (C₁₋₄alkyl)amino, anddi(C₁₋₄alkyl)amino; wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino anddi(C₁₋₄alkyl)amino is optionally substituted with (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, a 5 to 6membered heteroaryl, or a 5 to 6 membered heterocyclyl; and whereinpyridin-2-yl and pyridin-3-yl are optionally further substituted withN-morpholinyl; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), andA₁ is pyridin-4-yl or phenyl substituted with a substituent selectedfrom the group consisting of 4-C₁₋₆alkyl, 3,4-dichloro, and4-methanesulfonyl, A₂ is other than 4-methoxy-phenyl; provided that whenQ is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or —(CH₂)₅—, and A₁ ismethoxy, A₂ is other than phenyl substituted with 4-difluoromethoxy or4-methoxy; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—,and A₁ is pyrrol-1-yl, A₂ is other than 4-methoxy-phenyl; provided thatwhen Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is4-nitro-phenyl or ethoxy, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl,A₂ is other than 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl,3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;and provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;wherein a nitrogen atom of Ar₂ and Ar₄ is optionally substituted withoxo.
 17. The compound of claim 16 wherein Q is selected from the groupconsisting of (b) and (d) wherein: (b) is —NHCH₂—Ar₂ wherein Ar₂ ispyridin-2-yl, pyridin-3-yl, or pyrimidinyl; wherein Ar₂ is optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy, amino,and (C₁₋₄alkyl)amino; wherein the C₁₋₄alkyl group of (C₁₋₄alkyl)amino isoptionally substituted with di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, or hydroxy;and wherein pyridin-2-yl and pyridin-3-yl are optionally furthersubstituted with N-morpholinyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is pyridin-4-yl,4-C₁₋₆alkyl-phenyl, 3,4-dichloro-phenyl, or 4-methanesulfonyl-phenyl, A₂is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or —(CH₂)₅—, and A₁ ismethoxy, A₂ is other than 4-difluoromethoxy-phenyl or 4-methoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ isbenzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—, and A₁ ispyrrol-1-yl, A₂ is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is 4-nitro-phenylor ethoxy, A₂ is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl,3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; wherein anitrogen atom of Ar₂ and Ar₄ is optionally substituted with oxo.
 18. Thecompound of claim 17 wherein Q is —NHCH₂—Ar₂ wherein Ar₂ isunsubstituted pyridin-2-yl, 4,6-dimethyl-pyridin-3-yl,2-amino-pyridin-3-yl, or 2-((C₁₋₄alkyl)amino)-pyridin-3-yl; wherein theC₁₋₄alkyl group of (C₁₋₄alkyl)amino is optionally substituted withdi(C₁₋₄alkyl)amino, C₁₋₄alkoxy, or hydroxy; and wherein2-amino-pyridin-3-yl is optionally further substituted with 4,6-dimethylor 4-methoxy; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), andA₁ is pyridin-4-yl, 4-t-butyl-phenyl, 3,4-dichloro-phenyl, or4-methanesulfonyl-phenyl, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂— or —(CH₂)₅—,and A₁ is methoxy, A₂ is other than 4-difluoromethoxy-phenyl or4-methoxy-phenyl; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl),and A₁ is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₃—,and A₁ is pyrrol-1-yl, A₂ is other than 4-methoxy-phenyl; provided thatwhen Q is —NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is4-nitro-phenyl or ethoxy, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl,A₂ is other than 4-fluoro-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl,3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ isquinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl,2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl,2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; wherein anitrogen atom of Ar₂ is optionally substituted with oxo.
 19. A compoundof Formula (I)

wherein: A₁ is aryl, heteroaryl, or a benzofused heterocyclyl selectedfrom the group consisting of benzo[1,3]dioxalyl and2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, nitro, fluoro, chloro,iodo, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, and C₁₋₄alkylthio;provided that A₁ is other than 3,5-di-t-butyl-phenyl; L₁ is —(CH₂)_(r)—,wherein L₁ is optionally substituted with one to two substituentsindependently selected from the group consisting of C₁₋₄alkyl andC₂₋₄alkenyl and r is 1 or 2; D is —P-A₂; wherein P is —(CH₂)₁₋₂— when A₂is phenyl, benzofused heterocyclyl, heteroaryl, or C₃₋₈cycloalkyl;alternatively, P is —(CH₂)₄₋₆—, when A₂ is hydrogen, C₁₋₄alkoxy, orC₁₋₄alkoxycarbonyl; A₂ is hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,phenyl, benzofused heterocyclyl, heteroaryl other than pyridin-4-yl, orC₃₋₈cycloalkyl; wherein phenyl, heteroaryl and C₃₋₈cycloalkyl areoptionally substituted with one to two substituents independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, fluoro,chloro, halogenated C₁₋₆alkoxy, phenyl, N-isoindole-1,3-dione,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl, nitro, hydroxy,and C₁₋₆alkylcarbonylamino; provided that no more than one substituentof A₂ is phenyl or N-isoindole-1,3-dione; and provided that A₂ is otherthan 3,5-di-t-butyl-phenyl; W is N; Q is selected from the groupconsisting of (a)-(e) wherein: (a) is —NH(CH₂)₂—Ar₁ wherein Ar₁ ispyridinyl substituted with one to three C₁₋₄alkyl substituents or asubstituent selected from the group consisting of C₁₋₄alkoxy and amino;(b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl, pyrimidinyl,1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, orquinolinyl; such that the point of attachment to1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, andthe point of attachment to quinolinyl is at the 2, 3, or 4-position; andwherein Ar₂ is optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₄alkyl,trifluoromethyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; wherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino anddi(C₁₋₆alkyl)amino is optionally substituted with (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, a 5 to 6membered heteroaryl, or a 5 to 6 membered heterocyclyl; wherein anitrogen atom of the 5 to 6 membered heterocyclyl is optionallysubstituted with a C₁₋₄alkyl substituent; and wherein pyridin-2-yl andpyridin-3-yl are optionally further substituted with N-pyrrolidinyl,N-piperazinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, andphenyl; wherein the phenyl substituent of pyridin-2-yl and pyridin-3-ylis optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, andhalogen; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ ispyridin-4-yl, 4-C₁₋₄alkyl-phenyl or 3,4-dichloro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is benzotriazol-1-yl, A₂ is otherthan 4-difluoromethoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ is 4-nitro-phenyl,A₂ is other than 4-methoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), L₁ is —(CH₂)₂—, and A₁ ispyrazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl, and3-nitro-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is quinolin-8-yl,benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl,2-chloro-phenyl, 2-nitro-phenyl, 2-trifluoromethyl-phenyl,2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl,2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl,2,6-dichloro-phenyl, 2-chloro-4-fluoro-phenyl,2,6-difluoro-4-methoxy-phenyl, or 4-trifluoromethoxy-phenyl, A₂ is otherthan 4-difluoromethoxy-phenyl; and, provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 3-nitro-4-methoxy-phenyl,2,6-difluoro-4-methoxy-phenyl, or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; (c) is —CH₂NHCH₂—Ar₃, wherein W is N or CH, and Ar₃ ispyridinyl optionally substituted with amino; (d) is —(CH₂)₂—Ar₄, whereinAr₄ is pyridinyl, or pyrimidinyl; wherein Ar₄ is optionally substitutedwith one to two substituents independently selected from the groupconsisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; (e) is —CH═CH-pyridinyl; and wherein R₁ is hydrogenor C₁₋₄alkyl, and Ar₆ is pyridinyl or pyrimidinyl; wherein Ar₆ isoptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino,(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, halogen, and aminocarbonyl; andwherein the C₁₋₆alkyl group of (C₁₋₆alkyl)amino and di(C₁₋₆alkyl)aminois optionally substituted with amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₃₋₈cycloalkylamino, C₁₋₄alkoxy, or hydroxy;provided that when Q is —O—CH(R₁)—Ar₆, A₁ and A₂ are 4-methoxy-phenyl,and R₁ is hydrogen, Ar₆ is other than unsubstituted pyridin-2-yl or2-amino-pyridin-4-yl; wherein a nitrogen atom of Ar₁, Ar₂, Ar₃, Ar₄,Ar₆, and Ar₇ is optionally substituted with oxo; or an enantiomer, adiastereomer, a tautomer, and a pharmaceutically acceptable saltthereof.
 20. The compound of claim 19 wherein: A₁ is aryl, heteroaryl,or a benzofused heterocyclyl selected from the group consisting ofbenzo[1,3]dioxalyl and 2,3-dihydro-benzofuranyl; wherein aryl andheteroaryl are optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₃alkyl, methoxy,fluoro, chloro, trifluoromethyl, trifluoromethoxy, and methylthio; L₁ is—CH₂—; D is —P-A₂; wherein P is —CH₂— when A₂ is phenyl, benzofusedheterocyclyl, or heteroaryl; alternatively, P is —(CH₂)₄₋₆—, when A₂ isC₁₋₄alkoxy; A₂ is C₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or aheteroaryl other than pyridin-4-yl; wherein phenyl and heteroaryl areoptionally substituted with one to two substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, fluoro,chloro, halogenated C₁₋₄alkoxy, N-isoindole-1,3-dione, C₁₋₄alkylthio,C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, hydroxy, andC₁₋₄alkylcarbonylamino; provided that no more than one substituent of A₂is N-isoindole-1,3-dione; and provided that A₂ is other than3,5-di-t-butyl-phenyl; Q is selected from the group consisting of (b)and (d) wherein: (b) is —NHCH₂—Ar₂ wherein Ar₂ is pyridinyl,pyrimidinyl, or quinolinyl; such that the point of attachment toquinolinyl is at the 2, 3, or 4-position; and wherein Ar₂ is optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₄alkyl, trifluoromethyl, C₁₋₄alkoxy, amino,(C₁₋₄alkyl)amino, and di(C₁₋₄alkyl)amino; wherein the C₁₋₄alkyl group of(C₁₋₄alkyl)amino and di(C₁₋₄alkyl)amino is optionally substituted with(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylthio,hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 memberedheterocyclyl; and wherein pyridin-2-yl and pyridin-3-yl are optionallyfurther substituted with N-morpholinyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is pyridin-4-yl,4-C₁₋₃alkyl-phenyl, or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl),and A₁ is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl; provided that when Qis —NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is unsubstituted phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl, A₂ isother than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl, or3-nitro-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is quinolin-8-yl,benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl,2-chloro-phenyl, 2-trifluoromethyl-phenyl, 2-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl,2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or4-trifluoromethoxy-phenyl, A₂ is other than 4-difluoromethoxy-phenyl;and, provided that when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; (d) is—(CH₂)₂—Ar₄ and W is CH; wherein Ar₄ is pyridinyl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₆alkyl)amino, anddi(C₁₋₆alkyl)amino; wherein a nitrogen atom of Ar₂ and Ar₄ is optionallysubstituted with oxo; or an enantiomer, a diastereomer, a tautomer, anda pharmaceutically acceptable salt thereof.
 21. The compound of claim 20wherein: A₁ is substituted phenyl, heteroaryl, or a benzofusedheterocyclyl selected from the group consisting of benzo[1,3]dioxalyland 2,3-dihydro-benzofuranyl; wherein substituted phenyl is substitutedwith, and heteroaryl is optionally substituted with, one to threesubstituents independently selected from the group consisting ofC₁₋₃alkyl, methoxy, fluoro and methylthio; L₁ is —CH₂—; D is —P-A₂;wherein P is —CH₂— when A₂ is phenyl, benzofused heterocyclyl, orheteroaryl; alternatively, P is —(CH₂)₄₋₆—, when A₂ is C₁₋₄alkoxy; A₂ isC₁₋₄alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl other thanpyridin-4-yl; wherein phenyl and heteroaryl are optionally substitutedwith one to two substituents independently selected from the groupconsisting of C₁₋₄alkoxy, fluoro, halogenated C₁₋₄alkoxy, C₁₋₄alkylthio,C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, and hydroxy; Q is selectedfrom the group consisting of (b) and (d) wherein: (b) is —NHCH₂—Ar₂wherein Ar₂ is pyridin-2-yl, pyridin-3-yl, or pyrimidinyl; wherein Ar₂is optionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₄alkyl, trifluoromethyl,C₁₋₄alkoxy, amino, and (C₁₋₄alkyl)amino; wherein the C₁₋₄alkyl group of(C₁₋₄alkyl)amino is optionally substituted with di(C₁₋₄alkyl)amino,C₁₋₄alkoxy, or hydroxy; and wherein pyridin-2-yl and pyridin-3-yl areoptionally further substituted with N-morpholinyl; provided that when Qis —NHCH₂(2-amino-pyridin-3-yl), and A₁ is pyridin-4-yl,4-C₁₋₃alkyl-phenyl, or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; provided that when Q is —NHCH₂(2-amino-pyridin-3-yl),and A₁ is benzotriazol-1-yl, A₂ is other than 4-difluoromethoxy-phenyl;provided that when Q is —NHCH₂(2-amino-pyridin-3-yl), and A₁ is4-fluoro-phenyl, A₂ is other than 4-fluoro-phenyl; provided that when Qis —NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is —NHCH₂(pyridin-4-yl), andA₁ is 3,4-dichloro-phenyl, A₂ is other than 4-methoxy-phenyl; providedthat when Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is4-methoxy-phenyl, —P-A₂ is other than —(CH₂)₅-methoxy; provided thatwhen Q is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl,A₂ is other than 3-methoxy-phenyl or 3-nitro-phenyl; provided that whenQ is —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is quinolin-8-yl,benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl,2-chloro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl,2,6-dichloro-phenyl, 2-chloro-4-fluoro-phenyl, or2,6-difluoro-4-methoxy-phenyl, A₂ is other than4-difluoromethoxy-phenyl; and, provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is2,6-difluoro-4-methoxy-phenyl or 3,4-dichloro-phenyl, A₂ is other than4-methoxy-phenyl; wherein a nitrogen atom of Ar₂ and Ar₄ is optionallysubstituted with oxo; or an enantiomer, a diastereomers, a tautomer, anda pharmaceutically acceptable salt thereof.
 22. The compound of claim 21wherein: A₁ is substituted phenyl, benzotriazolyl, benzofuranyl,benzo[1,3]dioxalyl or 2,3-dihydro-benzofuranyl; wherein phenyl issubstituted at the 4-position with methoxy, fluoro, or methylthio; andwherein A₁ other than substituted phenyl is optionally substituted withone to two substituents independently selected from the group consistingof methyl, methoxy, fluoro and methylthio; L₁ is —CH₂—; D is —P-A₂;wherein P is —CH₂— when A₂ is phenyl, 2,3-dihydro-benzofuranyl, indolyl,benzofuranyl, pyridin-3-yl, or benzothiophenyl; alternatively, P is—(CH₂)₄₋₆—, when A₂ is C₁₋₄alkoxy; A₂ is C₁₋₄alkoxy, phenyl,2,3-dihydro-benzofuranyl, indolyl, benzofuranyl, pyridin-3-yl, orbenzothiophenyl; wherein A₂ other than C₁₋₄alkoxy is optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₁₋₄alkoxy, fluoro, fluorinated C₁₋₄alkoxy,C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, C₁₋₄alkoxycarbonyl, nitro, andhydroxy; Q is —NHCH₂—Ar₂ wherein Ar₂ is unsubstituted pyridin-2-yl,4,6-dimethyl-pyridin-3-yl, 2-amino-pyridin-3-yl, or2-((C₁₋₄alkyl)amino)-pyridin-3-yl; wherein the C₁₋₄alkyl group of(C₁₋₄alkyl)amino is optionally substituted with di(C₁₋₄alkyl)amino,C₁₋₄alkoxy, or hydroxy; and wherein 2-amino-pyridin-3-yl is optionallyfurther substituted with 4,6-dimethyl or 4-methoxy; provided that when Qis —NHCH₂(2-amino-pyridin-3-yl), and A₁ is pyridin-4-yl or4-methyl-phenyl, A₂ is other than 4-methoxy-phenyl; provided that when Qis —NHCH₂(2-amino-pyridin-3-yl), and A₁ is benzotriazol-1-yl, A₂ isother than 4-difluoromethoxy-phenyl; provided that when Q is—NHCH₂(2-amino-pyridin-3-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-fluoro-phenyl; provided that when Q is—NHCH₂(6-amino-pyridin-2-yl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-trifluoromethoxy-phenyl; provided that when Q is—NHCH₂(6-methyl-pyridin-2-yl), and A₁ is 4-methoxy-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(imidazo[1,2-a]pyridinyl), and A₁ is 4-fluoro-phenyl, A₂ is otherthan 4-methoxy-phenyl; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl), and A₁ is 4-methoxy-phenyl, —P-A₂ isother than —(CH₂)₅-methoxy; provided that when Q is—NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is 4-methoxy-phenyl, A₂ isother than 3-methoxy-phenyl or 3-nitro-phenyl; and provided that when Qis —NHCH₂(4,6-dimethyl-pyridin-3-yl) and A₁ is benzotriazol-1-yl, A₂ isother than 4-difluoromethoxy-phenyl; wherein a nitrogen atom of Ar₂ andAr₄ is optionally substituted with oxo; or an enantiomer, adiastereomers, a tautomer, and a pharmaceutically acceptable saltthereof.
 23. A pharmaceutical composition comprising a compound ofFormula (I)

selected from the group consisting of a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is

a compound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, Dis 4-methoxy-phenylmethyl, W is N, and Q is

a compound of Formula (I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂, D is—(CH₂)₅OCH₃, W is N, and Q is

a compound of Formula (I) wherein A₁ is 3,4-dichloro-phenyl, L₁ is CH₂,D is 4-methoxy-phenylmethyl, W is N, and Q is2-(pyridin-2-yl)ethyl-amino; a compound of Formula (I) wherein A₁ is3,4-dichloro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁ is4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-chloro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 5-amino-pyridin-2-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-chloro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 6-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4-amino-pyrimidin-5-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-quinolin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-(2-amino-pyridin-3-yl)-ethylamino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-N-pyrrolidinyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 2-N-piperazinyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-N-piperidinyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-methylamino-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-n-propylamino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-n-butylamino-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-N-morpholino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-N-thiomorpholino-pyridin-3-ylmethyl-amino; a compoundof Formula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-ethylamino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-N-morpholino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is1,2,3,4-tetrahydro-[1,8]naphthyridin-7-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzofuran-2-yl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methylthio-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 6-(4-fluoro-phenyl)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-hydroxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-amino-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-cyclohexylamino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is N-oxo-2-amino-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-hydroxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 2-n-propylamino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxycarbonyl-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methylcarbonylamino-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-trifluoromethoxy-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is pyridin-2-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is pyridin-3-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is pyridin-4-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 3-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-cyano-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-trifluoromethoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-ethoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-nitro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH(allyl), D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-aminocarbonyl-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is N-oxo-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-hydroxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 3-fluoro-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 2-amino-5-phenyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-4-methoxy-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 6-methyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 4-methyl-pyridin-2-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-ethyl-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is6-trifluoromethyl-pyridin-2-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 3-methyl-pyridin-2-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-methylthio-ethylamino)-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(3-methyl-butylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(tetrahydro-furan-2-ylmethyl)-amino)-pyridin-3-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(furan-2-ylmethyl-amino)-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(N-ethyl-pyrrolidin-2-ylmethyl-amino)-pyridin-3-ylmethyl-amino; acompound of Formula (I) wherein A₁ is phenyl, L₁ is CH₂CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is phenoxy, L₁ is CH₂CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 2,3-dihydro-benzo[1,4]dioxin-2-yl,L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-nitro-phenyl, L₁ is CH₂CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-(2-methoxy-ethylamino)-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methythio-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is pyridin-4-ylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is benzofuran-2-ylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 5-methoxy-n-pentyl, W isN, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is n-hexyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 3-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 3-cyano-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is3-nitro-phenylmethyl, W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino;a compound of Formula (I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁ isCH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-difluoromethoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-difluoromethoxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 2-ethyl-phenylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 2-trifluoromethoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2-cyano-phenylmethyl, W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino;a compound of Formula (I) wherein A₁ is 4-iodo-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-pyrazol-1-yl-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W isN, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-trifluoromethoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 2-methoxy-phenylmethyl, W is N, andQ is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 3-methoxycarbonyl-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2-(4-methoxy-phenyl)-ethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 6-methoxy-pyridin-3-ylmethyl, W isN, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is3-trifluoromethoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 3-trifluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methylthio-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is pyridin-4-ylmethyl, W is N, andQ is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is benzofuran-2-ylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is n-hexyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is6-methoxy-pyridin-3-ylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 2-trifluoromethoxy-phenylmethyl,W is N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-ethoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-nitro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH(allyl), D is 4-methoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 3-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 3-fluoro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is pyridin-4-ylmethyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W isN, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 6-amino-pyridin-2-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-fluoro-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-chloro-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is N-oxo-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is indol-3-yl, L₁ is CH₂CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 2,3-dihydro-benzo[1,4]dioxin-2-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N, andQ is 6-trifluoromethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 3-nitro-4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is benzofuran-5-ylmethyl, W is N, andQ is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-5-ylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is benzofuran-5-ylmethyl, W is N,and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-5-ylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methanesulfonyl-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methanesulfonyl-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is benzofuran-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzofuran-5-yl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-t-butoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is3-nitro-4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 3-nitro-4-methoxy-phenylmethyl,W is N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-4-ylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-4-ylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D isbenzothiophen-5-ylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-fluoro-phenoxy, L₁ is CH₂CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D isbenzothiophen-5-ylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 2-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is benzothiophen-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is benzothiophen-5-yl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W is N,and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is6-n-propylamino-pyridin-2-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-cyclohexylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-cyclohexylmethyl, W is N,and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is3,4-dichloro-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is4-(isoindol-1,3-dione-2-yl)-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 3-methoxycarbonyl-n-propyl, W isN, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is 2-pyridin-2-yl-ethylamino; acompound of Formula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D isindol-4-ylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is6-amino-pyridin-2-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 2,3-dihydro-benzofuran-5-ylmethyl,W is N, and Q is 2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; acompound of Formula (I) wherein A₁ is 4-pyrazol-1-yl-phenyl, L₁ is CH₂,D is 4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-iodo-phenyl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-fluoro-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methyl-phenyl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-trifluoromethyl-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-difluoromethoxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-cyano-phenyl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxycarbonyl-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is phenoxy, L₁ is CH₂CH₂, D is 4-difluoromethoxy-phenylmethyl, W isN, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-fluoro-phenoxy, L₁ is CH₂CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-[1,2,3]thiadiazol-4-yl-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-6-ylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-7-ylmethyl, W is N, and Qis 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is indol-7-ylmethyl, W is N, and Qis 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methylthio-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is benzothiophen-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is benzofuran-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methylthio-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzofuran-5-yl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2-cyano-phenyl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-hydroxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methylcarbonyloxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is benzofuran-5-yl, L₁ is CH₂, D is2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is imidazo[1,2-a]pyridin-8-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-hydroxymethyl-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2-methoxy-phenyl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl,W is N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-aminocarbonyl-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2,6-difluoro-4-methoxy-phenyl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzo[1,2,3]thiadiazol-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is methoxy, L₁ is (CH₂)₅, D is 4-methoxy-phenylmethyl, W is N, and Qis 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is methoxy, L₁ is (CH₂)₅, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 2,4-dimethoxy-phenylmethyl, W isN, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 4-methyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is3-fluoro-4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 3-fluoro-4-methoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2-fluoro-4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I) wherein A₁is 4-methoxy-phenyl, L₁ is CH₂, D is 2-fluoro-4-methoxy-phenylmethyl, Wis N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzo(1,3)dioxal-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2,3-dihydro-benzo[1,4]dioxin-6-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 2,3-dihydro-benzo[1,4]dioxin-6-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 4-methoxy-phenyl, L₁ is CH₂, D is2-methyl-2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is2-(N-piperidinyl)-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is 2-(pyridin-4-yl)-ethylamino; acompound of Formula (I) wherein A₁ is 1-methyl-1H-benzotriazol-5-yl, L₁is CH₂, D is 4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is benzo[1,2,3]thiadiazol-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is 3-fluoro-4-methoxy-phenyl, L₁ is CH₂, D is 4-methoxy-phenylmethyl,W is N, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is benzo(1,3)dioxal-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 1-methyl-1H-benzotriazol-5-yl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is 4-methoxy-phenyl, L₁ is CH₂, D is 5-methoxy-n-pentyl, W isN, and Q is 2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is2,3-dihydro-benzofuran-5-ylmethyl, W is N, and Q isN-oxo-2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound ofFormula (I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q is4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula (I) whereinA₁ is indol-5-yl, L₁ is CH₂, D is 4-difluoromethoxy-phenylmethyl, W isN, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula (I)wherein A₁ is indol-5-yl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, W isN, and Q is 4,6-dimethyl-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is indol-5-yl, L₁ is CH₂, D is 4-methoxy-phenylmethyl, Wis N, and Q is 2-amino-pyridin-3-ylmethyl-amino; a compound of Formula(I) wherein A₁ is 4-chloro-phenyl, L₁ is CH₂, D is4-methoxy-phenylmethyl, W is N, and Q is2-amino-pyridin-3-ylmethyl-amino; and a compound of Formula (I) whereinA₁ is 2,3-dihydro-benzofuran-5-yl, L₁ is CH₂, D is4-difluoromethoxy-phenylmethyl, W is N, and Q isN-oxo-2-amino-4,6-dimethyl-pyridin-3-ylmethyl-amino.
 24. Apharmaceutical composition comprising a compound or salt according toclaim 1 admixed with a pharmaceutically acceptable carrier, excipient ordiluent.
 25. A method of treating a condition in a mammal in which thecondition is affected by antagonism of prokineticin 1 receptors, whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of a compound or salt of claim 1, andwherein the condition is caused by irritable bowel syndrome (IBS,including diarrhea—predominant, as well as alternatingdiarrhea/constipation forms of IBS).
 26. The method of claim 25 whereinsaid therapeutically effective amount comprises a dose range of fromabout 0.1 mg to about 1,000 mg.
 27. The method of claim 26 wherein saidtherapeutically effective amount comprises a dose range of from about 50mg to about 1000 mg.
 28. The method of claim 27 wherein saidtherapeutically effective amount comprises a dose range of from about100 mg to about 1000 mg.
 29. A method of reducing and/or treatinginflammation that is a symptom of irritable bowel syndrome in theintestine of a mammal in need thereof, comprising administering to themammal a compound of claim 1, wherein the inflammation in the intestineis reduced.